A compound of the formula ##STR1## and pharmaceutically acceptable salts and prodrugs thereof wherein r1, r2, r3, r4, r5 and r6 are as defined below, methods and intermediates useful in the preparation thereof, pharmaceutical compositions thereof and methods of treatment therewith. The compounds of the above formula are useful in inhibiting oncogene products and as antitumor and anticancer agents.
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4. A compound of the formula ##STR7## and pharmaceutically acceptable salts thereof; wherein r1 and r2 together form a single bond; r3 and r4 together form a group of the formula
═J wherein J is selected from O and NOH: r5 is NR8 r9 wherein r3 and r9 are independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, (C3 -C8) cycloalkyl, (C2 -C8) alkenyl and (C2 -C8) alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8) alkoxyl, carboxyl, amidino, acylamino, and (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl groups selected from the group comprising furyl, tetrahydrofuryl; and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or r8 and r9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl; or r5 is r14 O wherein r14 is hydrogen or (C1 -C8)alkyl and r6 is hydrogen or a group of the formula ##STR8## wherein m is 0 or an integer from 1-5 and each r7 is independently selected from halo, azido, nitro, (C1 -C8)alkyl, C1 -C8 alkoxyl, phenyl and naphthyl, cyano and NR8 r9 wherein r8 and r9 are as defined above; with the proviso that when r1 and r2 together form a single bond and r3 is hydrogen and r4 OR10 and r10 is hydrogen, r5 cannot be OR14, wherein r14 is hydrogen or methyl, or NR8 r9 wherein HNR 8 r9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoyethylamine, aminobutylamine, adamantylmethylamine, cyclcopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycolamine, β-morpholinoethylamine, β-piperidinoethylamine, picolylamine, β-pyrrolidinoethylamine, β-pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine; and when r5 is OR14 and r10 is r11 C(═O), r11 cannot be methyl. 1. A compound of the formula ##STR5## and pharmaceutically acceptable salts thereof; wherein r1 and r2 are both hydrogen;
r3 is hydrogen and r4 is selected from the group consisting of OR10, NHR8 and halo wherein r10 is selected from the group consisting of hydrogen, r11 C(═O)--, and r11 SO2 -- and r12 r13 NSO2 NHC(═O)--, wherein r11 is selected from the group consisting of amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, hydroxy(C1 -C8)alkyl, phenyl and naphthyl; and r12 and r13 are selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; or r12 and r13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl and N-(C1 -C4)piperazinyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl; or r3 and r4 together form a group of the formula
═J wherein J is selected from O and NOH: r5 is NR8 r9 wherein r8 and r9 are independently selected from the group consisting of hydrogen, (C1 -C3)alkyl, (C3 -C8)cycloalkyl, (C2 -C8) alkenyl and (C2 -C8) alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8) alkoxyl, carboxyl, amidino, acylamino, and (C2 -C6)hetarocycloalkyl and (C2 -C6)heterocycloaryl groups selected from the group comprising imidazalolyl, furyl, tetrahydrofuryl; and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or r8 and r9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl; or r5 is r14 O wherein r14 is hydrogen or (C1 -C8)alkyl and r6 is hydrogen or a group of the formula ##STR6## wherein m is 0 or an integer from 1-5 ard each r7 is independently selected from halo, azido, nitro, (C1 -C8)alkyl, C1 -C8 alkoxyl, phenyl and naphthyl, cyano and NR8 r9 wherein r8 and r9 are as defined above; with the proviso that when r5 is OR14 and r10 is r11 C(═O), r11 cannot be methyl. 7. A method of inhibiting the growth of SKBr3 breast cancer cells comprising administering an effective amount of a compound of
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This invention relates to derivatives of geldanamycin, pharmaceutically acceptable salts and prodrugs of said derivatives, processes for Their preparation and antitumor and oncogene product inhibiting compositions containing said derivatives, salts and prodrugs as the active ingredients.
Oncogene products are proteins generated by cancer genes and are involved in the transformation of normal cells into cancer cells.
Geldanamycin is an antibiotic whose preparation and users were described in U.S. Pat. No. 3,595,955 (incorporated herein by reference).
Co-pending U.S. Patent application Ser. No. 07/817,235, filed Jan. 6, 1992 and assigned to Pfizer Inc. describes fermentation processes for preparing 4,5-dihydrogeldanamycin and its 18,21-hydroquinone.
Other derivatives of geldanamycin, and their use as antitumor agents are described in U.S. Pat. No. 4,261,989.
The present invention relates to compounds of the formula ##STR2## and pharmaceutically acceptable salts and prodrugs thereof here nafter, also, referred to as the active compounds; wherein R1 and R2 are both hydrogen or R1 and R2 together form a single bond; to as the active compounds;
wherein R1 and R2 are both hydrogen or R1 and R2 together form a single bond;
R3 is hydrogen and R4 is selected from the group consisting of --OR10, --NHR8 and halo;
wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--;
wherein R11 is selected from the group consisting of amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, hydroxy(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, protected hydroxy(C1 -C8)alkyl, phenyl and naphthyl; and
R12 and R13 are each independently selected from the group consisting of hydyrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl and N-(C1 -C4)piperazinyl;
and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl;
or R3 and R4 together form a group of the formula
═J
wherein J is selected from O and NOH;
R5 is NR8 R9 wherein R8 and R9 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkenyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyfl, carboxyl, amidino, acylamino, and (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl groups selected from the group comprising imidizaloly, furyl, tetrahydrofuryl; and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl;
or R5 is R14 O wherein R14 is hydrogen or (C1 -C4)alkyl;
and R6 is hydrogen or a group of the formula ##STR3## wherein m is 0 or an integer from 1-5 and each R7 is independently selected from halo, azido, nitro, (C1 -C8)alkyl, C1 -C8 alkoxyl, phenyl and naphthyl, cyano and NR8 R9 wherein R6 and R9 are as defined above; with the proviso that when R1 arid R2 together form a single bond R3 is hydrogen and R4 is OR10 wherein R10 is hydrogen then R5 cannot be OR14, wherein R14 is hydrogen or methyl, or NR8 R9 wherein HNR8 R9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycolamine, β-morpholinoethylamine, β-piperidinoethylamine, picolylamine, β-pyrrolidinoethylamine, β-pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine; and when R5 is OR14 and R10 is R11 C(═O), R11 cannot be methyl.
Preferably, the compounds of the invention are compounds of formula I wherein
1. R1 and R2 are each hydrogen;
a. R3 and R6 are each hydrogen and R4 is fluoro or OR10 wherein R10 is selected from hydrogen, R11 C(═O)--and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidonyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl, N-(C1 -C4)piperazinyl; wherein is as defined above; and R5 is OR14 or NR8 R9 wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkerlyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyfano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranchecl or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, ccarboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C6)alkyl; with the proviso that when R3 and R6 are hydrogen and R4 is OR10 wherein R10 is hydrogen, R14 is not methyl; or
b. R3 is hydrogen and R4 is selected from the group consisting of fluoro and OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyirolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl, N-(C1 -C4)piperazinyl; R6 is a group of the formula A wherein m is defined as above and R5 is OR14 or NR8 R9 wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkenyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxil, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, cairboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C8)alkyl; or
c. R6 is hydrogen, R3 and R4 together form a group of the formula
═J
wherein J is O or NOH; and R5 is OR14 or R8 R9 N wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkenyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl arid if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, cairboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C8)alkyl; or
d. R3 and R4 together form a group of the fomula
═J
wherein J is O or NOH;
R6 is a group of the formula A wherein m and R7 are as defined above; and R5 is R14 O or R8 R9 N wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkeyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl aind if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C8)alkyl; or
2. R1 and R2 together form a single bond and
a. R3 and R6 are each hydrogen, R4 is selected from the group consisting of fluoro and OR10 wherein R10 is selected from hydrogen, R11 (C═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl andi naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl, N-(C1 -C4)piperazinyl; and R5 is OR14 or NR8 R9 wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkeiiyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercipto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, arnidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C6)alkyl; with the proviso that when R10 is hydrogen then R5 cannot be OR14 wherein R14 is hydrogen or methyl or NR8 R9 wherein HNR8 R9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctyiamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidinyl, dimethylamine, aminoethylamine, diglycoamine, β-morpholinonethylamine, β-piperidinoethylamine, picolylamine, β-pyrrolidinoethylamine, β-pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine; or
b. R3 is hydrogen and R4 is selected from the group consisting of fluoro and OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl, N-(C1 -C4)piperazinyl; R6 is a group of the formula A wherein m is defined as above and R5 is OR14 or NR8 R9 wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkenyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, c:yano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkotyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C8)alkyl; or
c. R6 is hydrogen, R3 and R4 together form a group of the formula
═J
wherein J is O or NOH; and R5 is OR14 or NR8 R9 wherein
i. when R5 is R8 R9 N, R8 is hydrogen arid R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkenyl and (C2 -C6)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally subslituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C9)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C8)alkyl; or
d. R3 and R4 together form a group of the formula ═O or ═NOH; R6 is a group of the formula A wherein m and R7 are defined as above; and R5 is R14 O or R8 R9 N wherein
i. when R5 is R8 R9 N, R8 is hydrogen and R9 is selected from the group consisting of (C1 -C8)alkyl, (C3 -C8)cycloalkyl, (C2 -C8)alkenyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
ii. when R5 is R8 R9 N, R8 and R9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino and acylamino;
and iii. when R5 is R14 O, R14 is hydrogen or (C1 -C8)alkyl.
More preferred compounds of the invention are selected from the group consisting of compounds of the formula I wherein
1. R1, R2, R3 and R6 are each hydrogen, R4 is fluoro or OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl, and N-(C1 -C4)piperazinyl; and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, (C1 -C6)alkyl, (C2 -C8)alkenyl and (C2 -C8)alkynyl; wherein said alkyl, alkenyl and alkynyl groups are optionally substituted and said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8)alkylthio, optionally substituted amino, hydroxyl, (C1 -C8)alkoxyl, carboxyl, amidino, acylamino, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl and if comprising more than two carbon atc)ms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups;
2. R1, R2, R3 and R6 are each hydrogen, R4 is fluoro or --OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl, N-(C1 -C4)piperazinyl; and R5 is R8 R9 N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6) heterocycloaryl;
3. R1, R2, R3 and R6 are each hydrogen, R4 is fluoro or OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8) alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl and N-(C1 -C4)piperazinyl; and R5 is R14 O wherein R14 is (C1 -C8)alkyl with the proviso that when R10 is hydrogen R14 is not methyl;
4. R1 and R2 together form a single bond, R3 and R6 are each hydrogen, R4 is fluoro or OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogcen to which they are attached form a heterocyclic residue selected from the group consisting of aziridine, azetidine, pyrrolidone, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl and N-(C1 -C4)piperazinyl; and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl, optionally substituted (C3 -C6)cycloalkyl, optionally substituted (C2 -C6)alkenyl and optionally substituted (C2 -C6)alkynyl wherein the substituents of said alkyl aind alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl; with the proviso that when R10 is hydrogen then R5 cannot be NR8 R9 wherein HNR8 R9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoxyethylamine, aminobutylamine, benzyliumine, phenethylarnine, dimethylamine, aminoethylamine, diglycolamine, β-morpholinoethylamine, β-piperidinoethylamine, β-pyrrolidinoethylamine, β-pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine;
5. R1 and R2 together form a single bond, R3 and R6 are each hydrogen, R4 is fluoro or OR10 wherein R10 is selected from hydrogen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl and N-(C1 -C4)piperazinyl; and R5 is R8 R9 N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally sLibstituted with a group selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C3 -C8)heterocycloalkyl and (C4 -C8)heterocycloaryl; with the proviso that when R10 is hydrogen then NR8 R9 cannot be derived from ethyleneamine, pyrrolidine or piperidine;
6. R1 and R2 together form a single bond, R3 and R6 are each hydrogen, R4 is fluoro or OR10 wherein R10 is selected from hydrcgen, R11 C(═O)-- and R12 R13 NSO2 NHC(O)-- wherein R11 is selected from amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl aind naphthyl; wherein is as defined above; or R12 and R13 together with the nitrogen to which they are attached form a heterocylic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1 -C4)alkylpiperidinyl and N-(C1 -C4)piperazinyl; and R5 is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl; with the proviso that when R10 is hydrogen R14 cannot be hydrogen or methyl and when R10 is R11 C(═O), R11 cannot be methyl;
7. R1, R2 and R6 are each hydrogen, R3 and are R4 together form a group selected from ═O and ═NOH and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl or optionally substituted (C3 -C6)cycloalkyl (C2 -C6)alkenyl and (C2 -C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
8. R1, R2 and R6 are each hydrogen, R3 and R4 logether form a group selected from ═O and ═NOH and R5 is R8 R9 N wherein R8 ard R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
9. R1, R2 and R6 are each hydrogen, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl;
10. R1 and R2 together form a single bond, R6 is hydrogen, R3 and R4 together form a group selected from ═O and ═NOH;
and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl or optionally substituted (C3 -C6)cycloalkyl, (C2 -C6)alkenyl and (C2 -C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
11. R1 and R2 together form a single bond, R6 is hydrogen, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R8 R9 N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
12. R1 and R2 together form a single bond, R6 is hydrogen, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl;
13. R1, R2 and R3 are each hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4 fluoro or OR10 ; wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--; wherein R11 is selected from the group consisting of amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl; and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl, optionally substituted (C3 -C6) cycloalkyl, optionally substituted (C2 -C6)alkenyl and optionally substituted (C2 -C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
14. R1, R2 and R3 are each hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4 is fluoro or OR10 ; wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--; wherein R11 is selected from the group consisting of amino, (C1 -C8)alkiyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with at least one residue selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azid, and (C1 -C8)alkoxyl; and R5 is R8 R9 N wherein R3 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with at least one group selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
15. R1, R2 and R3 are each hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4 is OR10 or fluoro; wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--; wherein R11 is selected from the group consisting of amino, (C1 -C8)allkyl, amino(C1 -C8)alkyl, protected amino(C3 -C6)alkyl, phenyl and naphthyl; R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, morpholino, N-methylpiperazinyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl; and R5 is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl;
16. R1 and R2 together form a single bond, R3 is hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4 is OR10 or fluoro; wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--; wherein R11 is selected from the group c)nsisting of amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl and said alkyl, phenyl and naphthyl groups may be substituted with one or more substituents selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl;
and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl, optionally substituted (C3 -C6)cycloalkyl, optionally substituted (C2 -C6)alkenyl and optionally substituted (C2 -C6)alkynyl wherein the substituents of said alkyl and alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
17. R1 and R2 together form a single bond, R3 is hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4 is OR10 or fluoro; wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--; wherein R11 is selected from the group consisting of amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C1 -C8)alkyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl; and R5 is R8 R9 N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with at least one group selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
18. R1 and R2 together form a single bond, R3 is hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R4 is OR10 or fluoro; wherein R10 is selected from the group consisting of hydrogen, R11 C(═O)--, R11 SO2 -- and R12 R13 NSO2 NHC(═O)--; wherein R11 is selected from the group consisting of amino, (C1 -C8)alkyl, amino(C1 -C8)alkyl, protected amino(C1 -C8)alkyl, phenyl and naphthyl; and R12 and R13 are each independently selected from the group consisting of hydrogen, (C1 -C8)alkyl, amino(C1 -C8)alkyl, dimethylamino(C1 -C8)alkyl, cyclo(C3 -C8)alkyl, phenyl and naphthyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1 -C8)alkyl, halo, nitro, amino, azido and (C1 -C8)alkoxyl; and R is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl;
19. R1 and R2 are each hydrogen, R6 is a group of the formula A wherein m is and R7 are defined above, R3 and are R4 together form a group selected from ═O and ═NOH and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl, optionally substituted (C3 -C6)cycloalkyl, optionally substituted (C2 -C6)alkenyl and optionally substituted (C2 -C6)alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)hetcerocycloalkyl and (C2 -C6)heterocycloaryl;
20. R1 and R2 are each hydrogen, R6 is a group of the formula A wherein m and R 7 are as defined above, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R8 R9 N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocglcloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
21. R1 and R2 are each hydrogen, R6 is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl;
22. R1 and R2 together form a bond, R6 is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R8 R9 N wherein R8 is hydrogen and R9 is selected from hydrogen, optionally substituted (C1 -C6)alkyl or optionally substituted (C3 -C6)cycloalkyl, (C2 -C6)alkenyl and (C2 -C6)alkynyl wherein the substituents of said ilkyl and alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl;
23. R1 and R2 together form a bond, R6 is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group ,elected from ═O and ═NOH and R5 is R8 R9 N wherein R8 and R9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C1 -C6)alkoxyl, (C1 -C6)alkylthio, (C2 -C6)heterocycloalkyl and (C2 -C6)heterocycloaryl; or
24. R1 and R2 together form a bond, R6 is a group of the formula A wherein m and R7 are as defined above, R3 and R4 together form a group selected from ═O and ═NOH and R5 is R14 O wherein R14 is hydrogen or (C1 -C8)alkyl.
Most preferred compounds of the invention are selected from the group consisting of
17-Amino-4,5-dihydro-17-demethoxy-geldanamycin;
17-Methylamino-4,5-dihydro-17-demethoxygeldanamycin;
17-Cyclopropylamino-4,5-dihydro-17-demethoxygeldanarnycin;
17-(2'-Hydroxyethylamino)-4,5-dihydro-17-demethoxygelclanamycin;
17-(2-Methoxyethylamino)-4,5-dihydro-17-demethoxygeld anamycin;
17-(2'-Fluoroethylamino)-4,5-dihydro-17-demethoxygeldanamycin;
17-[s-(+)-2-Hydroxypropylamino]-4,5-dihydro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-4,5-dihydro-17-demethoxygeldanamycin;
17-(3-Hydroxyazetidin-1-yl)-4,5-dihydro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-4,5-dihydro-11-α-fluoro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-17-demethoxygeldanamycin;
17-(2'-Cyanoethylamino)-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-17-demethoxygeldanamycin;
17-Amino-22-(2'-methoxyphenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(3'-methoxyphenacyl)-17-demethoxygeldanetmycin;
17-Amino-22-(4'-chlorophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(3',4'-dichlorophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycin;
17-Amino-22-(4'-azido-3'-iodophenacyl)-17-demethoxygeldanamycin;
17-Amino-11-α-fluoro-17-demethoxygeldanamycin;
17-Allylamino-11-α-fluoro-17-demethoxygeldanamycin;
17-Propargylamino-11-α-fluoro-17-demethoxygeldanamycin;
17-(2'-Fluoroethylamino)-11-α-fluoro-17-demethoxygeldanamycin;
17-Azetidin-1-yl-11-(4'-azidophenyl)sulfamylcarbonyl-17-demethoxygeldanamyc in;
17-(2'-Fluoroethylamino)-11-keto-17-demethoxygeldanamycin;
17-Azetidin-1-yl-11-keto-17-demethoxygeldanamycin; and
17-(3'-Hydroxyazetidin-1-yl)-11-keto-17-demethoxygeldanamycin.
This invention also relates to a pharmaceutical composition comprising an antitumor or oncogene product inhibiting or cancer preventing or treating effective amount of a compound of the formula I, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method of inhibiting an oncogene product in a mammal, including a human, comprising administering to said mammal an oncogene product inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
This invention also relates to a method of inhibiting an ErbB-2, src, Ick, fyn or abl oncogene product in a mammal, including a human, comprising administering to said mammal an ErbB-2, src, Ick, fyn or abl oncogene product inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
This invention also relates to a method of treating or preventing cancer in a mammal, including a human, comprising administering to said mammal an antitumor or oncogene product inhibiting effective amount of a compournd of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
This invention also relates to a method of preventing or inhibiting the growth of a tumor in a mammal, including a human, comprising administering to said mammal an antitumor effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
This invention also relates to a method of inhibiting growth factors that play an important role in uncontrolled cell proliferation such as the EGF receptor, the NGF receptor, the PDGF receptor and the insulin receptor in a mammal, including a human, comprising administering to said mammal a growth factor inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
The pharmaceutically acceptable salts of the present invention are those which are non-toxic at the dosages administered. Since compounds of the invention may contain basic groups, acid addition salts are possible. Pharmaceutically acceptable acid addition salts include, for example, the hydrochloride, hydrObromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactalte, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluConate and saccharate salts.
Typical pharmaceutically acceptable anions include the acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetixte; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsNIlate; hexylresorcinate; hydroxynaphthoate; iodide; isothionate; lactate; lactobionate; malate; maleate; mandelate; mesylate; methylbromide; methyinitrate; methylsulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate; polygAlacturonate; salicylate; stearate; subacetate; succinate; sulfate; tannate; tartrate; and teoclate.
Unless indicated otherwise, the alkyl, alkoxy, and alkenyl moieties referred to herein may comprise linear, branched and cyclic moieties and combinations thereof and the term "halo" includes fluoro, chloro, bromo and iodo. It will be understood, however that a group comprising only 1 or 2 atoms cannot be branched or cyclic. Examples of alkyl groups are methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl and cyclohexyl.
Furthermore, unless otherwise indicated optionally substituted means comprising from zero to the maximum number of substituents, e.g., 3 for a methyl group, 1 for a hexyl group and 5 for a phenyl group.
The active compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
The following reaction schemes illustrate the preparation of the compounds of the formula I. In the reaction schemes and discussion that follow, except where otherwise indicated, R1, R2, R4, R5, R6, R7, R8, R9 and R10 are defined as for formula I above. ##STR4##
As shown in Scheme 1 compound 2 is formed by condensation of the geldanamyacin or 4,5-dihydrogeldanamyacin 1 with an amine R8 R9 NH. This reaction is generally carried out by mixing the amine and the ansamycin in an inert solvent such as chloroform, methylene chloride, N,N-dimethylformamide (DMF), pyridine, acetonitrile, tetrahydrofuran (THF) or a lower alcohol, preferably chloroform or methylene chloride, at a temperature from about ambient temperature to the reflux temperature of the solvent, preferably from about ambient temperature to about 65° C.
The conversion of 1 or 2 to 3 is generally carried out by oxidizing 2 with standard oxidizing reagents such as pyridinium chlorochromate in methylene chloride, pyridinium dichromate in DMF, oxalyl chloride/dimethyl sulfoxide (DMSO) in methylene chloride, Dess-Martin periodinane in chloroform, and Jones reagent in acetone, preferably Dess-Martin periodinane in chloroform at reflux. Those skilled in the art will recognize that these reagents can be used with additional, inert solvents and at temperatures ranging from -60°C to the reflux temperature of tle solvent.
The conversion of 3 to 4 is generally carried out by reacting 3 with hydroxylamine hydrochloride in the presence of a base (e.g., sodium acetate, pyridine, sodium carbonate, sodium hydroxide, potassium carbonate, and triethylamine) in water or a lower alcohol solvent at about 0°C to about 100°C Prefearably, 3 is combined with hydroxylamine hydrochloride in the presence of triethylamine in ethanol at room temperature.
The conversion of 3 to 5 is generally carried out under standard reductive amination conditions such as combining the amine and 3 in an inert solvent (e.g., halogenated (C1 -C6) alkanes and (C1 -C6)alcohols) with a suitable reducing agent (e.g., sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and formic acid), optionally in the presence of a dehydrating agent (e.g., sodium sulfate, molecular sieves, and calcium sulfate), at temperatures ranging from about ambient temperature to the reflux temperature of the solvent. Preferably, the reaction is carried out by combining 3, the amine, sodium triacetoxyborohydride and sodium sulfate in 1,2-dichloroethane at ambient temperature.
As shown in Scheme 2 compound 1 or 2 can be selectively 22-N-alkylated to afford 6 by treatment with a base, such as a (C1 -C6) alkoxide, in a polar solvent, for instance dimethylformamide or dimethyl sulfoxide, followed by reaction with an appropriate alkylating agent, for example, an alkyl halide. Reaction temperatures are maintained between about 5 and about 65°C, optimally from abclut 5 to about 25°C Alternatively, the compound 1 or 2 can be reacted with anhydrous p)otassium carbonate and the alkyl halide in acetone at reflux.
Compound 7 can be prepared by treating compound 1 or 2 with diethylaminosulfurtrifluoride (DAST). This reaction is performed in AN inert solvent (e.g., methylene chloride, chloroform and dichloroethane) at low temperature of about -78° to about 0°C, preferably from about -78° to about -50°C OptiMally, the reaction is quenched at low temperature with dilute aqueous base, for example 5% sodium bicarbonate.
Compound 1 or 2 can be converted to 11-O-acyl or 11-O-sulfonyl derivatives by treatment with acylating or sulfonating agents in the presence of non-nucleophilic bases. The acylating agents include acid anhydrides, halides and isocyanates. Sulfonating agents include sulfonyl halides and anhydrides.
Solvents used in these reactions include a wide variety of aprotic polar and non-polar media, for example, acetone, chloroform, ethyl acetate, DMF, pyridine, tetrahydrofuran. Bases used include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine and 4-dimethylaminopyridine. If desired, compounds 3-7 wherein R5 is R14 O may be converted to compounds 3-7 wherein R5 is R8 R9 by the method for converting 1 to 2 in Scheme 1.
The preparation of other compounds of the formula I not s;pecifically described above can be accomplished using combinations of the above reactions that will be clear to those skilled in the art in view of the foregoing disclosure.
The compounds of formula I and their pharmaceutically acceptable salts are useful as antitumor agents (including, but not limited to anticancer agents) and oncogene product inhibitors. They are useful, for example, in inhibiting the ErbB-2, src, Ick, fyn and abL oncogene products. They are also useful in inhibiting certain growth factors that play an important role in uncontrolled cell proliferation such as the EGF receptor, the NGF receptor, the PDGF receptor and the insulin reaceptor.
The ability of the active compounds to inhibit the ErbB-2 oricogene product may be determined by the following method for determining the p185 concentrations in SKBr3 cells.
SKBr3 human breast cancer cells, obtained from the ATCC, Rockville, Md. were seeded in 8 well tissue culture plates (9.5 cm2 /well, Falcon, Becton Dickenson, Lincoln Park, N.J.) at 5×105 cells/well in 2 ml McCoys medium, supplemented with 10% fetal calf serum and glutamine. Cells were allowed to attach overnight at 37°C in a 5% CO2 atmosphere.
The compounds are dissolved in DMSO and tested over a range of concentrations by addition to the medium, followed by incubation at 37°C for 6 hours. At the end of the incubation, the medium is aspirated from the well, and the cells are washed twice with 2 ml of TNK buffer (50 mM tris (hydroxymethyl)aminomethane hydrochloride, 140 mM NaCL, 3.3 mM KCL, 0.5 mM sodium orthovanadate, adjusted to pH 7.4). The cells are then lysed by addition of 250 μl boiling Lalammli sample buffer (140 mM tris(hydroxymethyl)aminomethane hydrochloric acid, pH 6.8, 5.7% sodium dodecyl sulfate, 29% glycerol) with shaking. The cell lysate is transferred to a tube and then placed in a boiling water bath for 5 mins. The lysates are then sonicated with a probe sonicator and stored at -70°C until analysis.
The p185 concentration of each sample may be determined by standard immunoblotting procedures essentially as described by Harlow and Lane (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988). A standard portion of each sample is mixed with dithiothreitol (10% added of a 1M solution), and then a portion corresponding to ∼10 μg of protein is blotted onto a nitrocellulose membrane (BA-S, Schleicher and Schuell, Keene, New Hampshire) equilibrated with rinse buffer (10 mM Tris hydrochloric acid pH 7.4, 150 mM NaCL) by use of A dot blot apparatus (Mini-fold, Schleicher and Schuell, Keene, New Hampshire) with an underlayer of filter paper. The wells are rinsed with 200 μl of a rinse buffer, blocked by incubation with a blocking buffer (5% bovine serum albumin, 1% ovalbumin in rinse buffer), and then incubated for 4 to 12 hours with a 1:1000 dilution of NT1, an eLffinity purified rabbit polyclonal antibody raised by standard methods (Harlow and Lane, Antibodies, A Laboratorv Manual, Cold Spring Harbor Laboratory, 1988) against a peptide representing the C-terminal domain of human p185 (sequence, TAENPEYLGLDVPV, by the standard 1 letter amino acid code). The membrane is then rinsed twice for 10 minutes with rinse buffer and once for 10 minutes in rinse buffer with 0.05% Triton X-100, and then twice more for 10 minutes in rinse buffer. The membrane is then incubated with a 1:3000 dilution of horseradish peroxidase labeled donkey anti-rabbit antibody (Amersham, Arlington Heights, Ill.) in a rinse buffer with shaking for 20-45 minutes. The membrane is then again rinsed twice for 10 minutes in the rinse buffer, once for 10 minutes in the rinse buffer with 0.05% Triton X-100, And then twice more for 10 minutes in the rinse buffer. The p185 is then visualized with the ECL Detection Kit (Amersham, Arlington Heights, Ill.) and recorded with Hyperiilm-ECL (Amersham, Arlington Heights, Ill.). The p185 is then estimated by densitometric analysis of the film. IC50 values are determined by reference to the p185 contert of samples of cells exposed only to vehicle (DMSO) and measured as described.
The ability of the active compounds to inhibit the ErbB-2 oncogene product may be determined by following the method of Kamps et al., Oncogene, 2, 305-315 (1988) for determining the phosphorylation of p185 in SKBR3 and other ErbB-2 transformed cell lines.
The ability of the active compounds to inhibit the growth of certain human carcinoma cells may be determined by the methods of Alley et al., Cancer Research 48, 589-601 (1988) using SKBr3 and MCF7 cell lines. This refere-nce is incorporated herein in its entirety.
When the compounds of the formula I and their pharmaceutically acceptable salts are used as antiproliferative agents, such as anticancer agents, they can be administered to a mammalian subject either alone or, preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice. The compounds can be administered orally or parenterally. Parenteral administration includes intracenous, intramuscular, intraperitoneal, subcutaneous and topical.
In general, the active compounds are administered in dosage ranging from about 0.1 mg to about 20 mg per kg of body weight as needed (e.g., every 4 to 6 hours), preferably from about 0.1 to about 15 mg per kg of body weight; variations will necessarily occur depending upon the condition of the subject being treated and the particular compound and dosage form being administered. It is to be noted that these compounds may be administered in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
The active compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in, e. g., the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
The hard capsules for oral use may also be presented as gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or whereas the soft capsules may be presented as gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methiylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil; a mineral oil such as liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides such as example soy bean and lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulation may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to 1he known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The active compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
For topical use, creams, ointments, Jellies, solutions cr suspensions, etc., containing the active compounds of the invention are employed.
For administration by inhalation, the active compounds of the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer. The preferred composition for inhalation is a powder which may be formulated as a cartridge from which the powder composition may be inhaled with the aid of a suitable device. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.
One or more other active compounds may be added to the formulations described above to provide formulations for combination therapy. Such compounds include cytostatic, cytotoxic and antiemetic agents conventionally used in cancer chemotherapy, such as adriamycin.
The following examples illustrate the invention but are not to be construed as limiting the same. All melting points are uncorrected. In the Examples, "BOC" refers to t-butoxycarbonyl.
PAC General MethodsHigh pressure liquid chromatography (HPLC) was performed at 1.0 mL/minute with 254 nm detection on a 250×4.6 mm Dupont Zorbax Sil (trademark) column eluted isocratically by a two-pump/mixer system supplying the indicated mixture of 1% methanol in ethyl acetate and hexanes respectively. Samples to be thus analyzed are dissolved in an HPLC eluent. The HPLC retention times are reported followed by the ethylacetate/hexane ratio in parentheses. The terms "concentrated in vacuo" and "coevaporated" refer to removal of solvent at water aspirator pressure on a rotary evaporator with a bath temperature of less than 40°C
PAC 17-Isopropylamino-4,5-dihydro-17-demethoxcygeldanamycinTo 4,5-dihydro-geldanamycin (75 mg, 0.13 mmol) in CHCl3 was added isopropylamine (68 μL, 0.80 mmol) and the reaction stirred at room temperature for 24 hours at which time TLC analysis indicated the reaction was not complete. The reaction mixture was then heated at reflux for 3 hours. The solvent was removed by rotary evaporation and the purple residue partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layer was dried, the solvent removed by rotary evaporation, and the crude material purified by column chromatography (silica gel, 9:1 CH2 Cl2 :methanol) to give the title compound as a purple solid; Yield 56 mg (72%), mp 114-115°C; 1 H-NMR (300 MHz, CDCl3)δ0.95 (d, 3 H, J=7 Hz), 1.00 (d, 3 H, J=7 Hz), 1.2 (d, 3 H, J=7 Hz), 1.35 (d, 3 H, J=7 Hz), 1.7 (s, 3 H), 1.9 (s, 3 H), 2.2 (dd, 1 H, J=14, 7), 2.4 (dd, 1 H, J=14 Hz, 7 Hz), 2.5-2.8 (m, 1 H), 3.3 (m, 1 H), 3.35 (s, 3 H), 3.4 (s, 3 H), 3.4-3.5 (m, 1 H), 3.6 (d, 1 H, J=9 Hz), 3.7 (lr s,1 H), 4.1 (m, 1 H), 4.95(s,2H),5.2(d,1 H,J=7Hz Hz),5.75(d,1 H, J=9 Hz),6.2(t,1 H, J=9 Hz), 7.1 (s, 1 H), 9.3 (br s, 1 H); mass spectrum m/z 612 (M+Na).
The compounds of Examples 2-14 were prepared from 4,5-dihydro-geldanamycin and the appropriate amines using the conditions described above.
PAC 17-Amino4,5-dihydro-17-demethoxygeldanamycin1 H-NMR (300 MHz, CDCl3)δ0.95 (m, 6 H), 1.5-1.8 (m, 8 H, contains methyl singlet), 1.85 (s, 3 H), 2.0 (m, 1 H), 2.35 (m, 2 H), 2.6 (m, 1 H), 2.7 (m, 1 H), 3.2-3.5 (m, 8 H, contains 2 methyl singlets), 3.8 (m, 2 H), 5.0 (br s, 2 H), 5.1 (d, 1 H, J=4 Hz), 5.6 (br s, 2 H), 5.7 (d, 1 H, J=10 Hz), 6.2 (t, 1 H, J=7 Hz), 7.05 (s, 1 H), 9.15 (s, 1 H); mass spectrum m/z 547 (M+); Analysis calculated for C28 H41 N3 O8∅5 H2 : C, 60.42; H, 7.60; N, 7.55%. Found: C, 60.42; H, 7.45; N, 7.51%.
PAC 17-Methylamino-4,5-dihydro-17-demethoxygeldanamycinMp 181°C; 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H), 1.5-1.8 (m, contains methyl singlet, 9 H), 1.9 (s, 3 H), 2.3-2.8 (m, 5 H), 3.2 (d, 3 H, J=7 Hz), 3.3-3.45 (m, contains 2 methyl singlets, 8 H), 3.45-3.55 (m, 1 H), 3.6 (br d, 1 H, J=7 Hz), 3.75 (br s, 1 H), 4.7 (br s, 2 H), 5.2 (d, 1 H, J=7 Hz), 5.8 (d, 1 H, J=10 Hz), 6.25 (t, 1 H, J =7 Hz), 6.4-6.55 (m, 1 H), 7.15 (s, 1 H), 9.3 (br s, 1 H); mass spectrum m/z 561 (M+); Analysis calculated for C29 H43 N3 O8 : C, 62.01; H, 7.72; N, 7.48%. Found: C, 61.60; H, 7.73; N, 7.16%.
PAC 17-Cyclopropylamino-45-dihydro-17-demethoxygeldanamycinMp 146-147°C; 1 H-NMR (300 MHz, CDCl3)δ0.6-0.9 (m, 4 H), 0.9-1.1 (m, 6 H), 1.5-1.8 (m, contains methyl singlet, 6 H), 1.9 (s, 3 H), 2.3-2.5 (m, 2 H), 2.5-2.8 (m, 2 H), 2.8-3.0 (m, 2 H), 3.2-3.4 (m, contains 2 methyl singlets, 8 H), 3.4-3.5 (m, 1 H), 3.5-3.7 (br d, 2 H), 4.9 (br s, 2 H), 5.15 (d, 1 H, J=7 Hz), 5.75 (d, 1 H, J=10 Hz), 6.2 (t, 1 H, J=7 Hz), 6.35 (d, 1 H, J=3), 7.1 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 587 (M+); Analysis calculated for C31 H45 N3 O8∅5 H2 O: C, 62.40; H, 7.77; N, 7.04%. Found: C, 62.55; H, 7.61; N, 6.83%.
PAC 17-Allylamino-4,5-dihydro-17-demethoxygeldanamycinMp 205°C; 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H, 2 methyl doublets), 1.5-1.8 (m, 8 H, contains methyl singlet), 1.9 (s, 3 H), 2.2-2.5 (m, 3 H), 2.5-2.8 (m, 2 H), 3.2-3.5 (m, 8 H, contains 2 methyl groups), 3.6 (d, 1 H, J=7 Hz), 4.1 (m, 2 H), 4.8 (s, 2 H), 5.2 (d, 1 H, J=7Hz), 5.25 (d, 1 H, J=10 Hz), 5.3 (s, 1 H), 5.75 (d, 1 H, J=10 Hz), 5.9 (m, 1 H), 6.25 (t, 1 H, J=7 Hz), 6.4 (br t, 1 H), 7.25 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 610 (M+Na); Analysis calculated for C31 H45 N3 O8∅5 H2 O: C, 62.40; H, 7.77; N, 7.04%. Found: C, 62.26; H, 7.83; N, 6.75%.
PAC 17-(2'-Hydroxnethylamino)-4,5-dihydro-17-demethoxygeldanamycinMp 129°C (foam); 1 H-NMR (300 MHz, CDCl3)δ0.9-1.1 (m, 6 H), 1.6-1.8 (m, contains methyl singlet, 8 H), 1.9 (s, 3 H), 2.3-2.5 (m, 3 H), 2.7-2.8 (m, 2 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.55-3.65 (d, 1 H, J=10 Hz), 3.65-3.8 (m, 2 H), 3.8-4.0 (m, 1 H), 4.85 (br s, 2 H), 5.15 (d, 1 H, J=4 Hz), 5.78 (d, 1 H, J=10Hz), 6.2 (t, 1 H, J=7 Hz), 7.1 (s, 1 H), 9.21 (s, 1 H); mass spectrum m/z 591 (M+); Analysis calculated for C30 H45 N3 O9 : C, 60.90; H, 7.67; N, 7.10%. Found: C, 60.40; H, 7.89; N, 6.63%.
PAC 17-(2'-Methoxyethylamino)-4,5-dihydro-17-demethoxygeldanamycinMp 115°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.8-1.0 (m, 6 H), 1.5-1.8 (m, contains broad methyl singlet, 7 H), 1.85 (br s, 3 H), 2.2-2.5 (m, 3 H), 2.5-2.8 (m, 2 H), 3.2-3.5 (m, contains 3 methy singlets, 12 H), 3.5-3.8 (m, 5 H), 5.0 (br s, 2 H), 5.15 (d, 1 H, J=7 Hz), 5.7 (d, 1 H, J=10 Hz), 6.2 (brt, 1 H, J=7 Hz), 6.55 (br s, 1 H), 7.1 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 605 (M+); Analysis calculated for C31 H47 N3 O9 : C, 61.47; H, 7.82; N, 6.94%. Found: C, 61.0; H, 7.58; N, 6.71%.
PAC 17-(2'-Fluoroethylamino)-4,5-dihydro-17-demethoxygeldanamycinMp 157°C (foam); 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H), 1.6-1.8 (m, contains methyl singlet, 8 H), 1.9 (s, 3 H), 2.0-2.1 (br s, 1 H), 2.2-2.5 (m, 3 H), 2.6-2.8 (m, 2 H), 3.2-3.7 (m, contains 2 methyl singlets, 8 H), 3.7-4.0 (m, 2 H), 4.55 (t, 1 H, J=7Hz), 4.7-4.85 (m, 3 H), 5.2 (d, 1 H, J=7 Hz), 5.8 (d, 1 H, J=10 Hz), 6.25 (t, 1 H, J=7 Hz), 6.4 (t, 1 H, J=7 Hz), 7.15 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 593 (M+).
PAC 17-(2'-Methylthioethylamino)-4,5-dihydro-17-demethoxygeldanamycinMp 110°C (foam); 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H), 1.5-1.75 (m, contains methyl singlet, 8 H), 1.85 (s, 3 H), 2.1 (s, 3 H), 2.2-2.4 (m, 3 H), 2.5-2.8 (m, 4 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.5-3.8 (m, 4 H), 5.0 (s, 2 H), 5.15 (d, 1 H, J=4 Hz), 5.75 (d, 1 H, J=10 Hz), 6.2 (t, 1 H, J=7 Hz), 6.6 (t, 1 H, J=4 Hz), 7.1 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 644 (M+Na); Analysis calculated for C31 H47 N3 O8 S∅5 H2 O: C, 59.03; H, 7.67; N, 6.66%. Found: C, 58.87; H, 7.67; N, 6.60%.
PAC 17-[s-(+)-2'-Hydroxypropylaminol]-4,5-dihydro-17-demethoxygeldanamycin1 H-NMR (300 MHz, CDCl3)δ0.95 (d, 3 H, J=7 Hz), 1.0 (d, 3 H, J=7 Hz), 1.3 (d, 3 H, J=7 Hz), 1.5-1.75 (m, contains methyl singlet, 6 H), 1.85 (s, 3 H), 2.25-2.45 (m, 2 H), 2.6-2.7 (m, 1 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.5-3.7 (m, 2 H), 4.05 (m, 1 H), 4.9 (s, 2 H), 5.15 (d, 1 H, J=7 Hz), 5.8 (d, 1 H, J=7 Hz), 6.2 (t, 1 H, J=7 Hz), 6.7 (br s, 1 H), 7.05 (s, 1 H), 9.2 (br s, 1 H); mass spectrum m/z 605.3(M+).
PAC 17-(2'-Cyanoethylamino)-4,5-dihydro-17-demethoxygeldanamycinMp 130-140°C (foam); 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H), 1.5-1.8 (m, contains methyl singlet, 8 H), 1.9 (s, 3 H), 2.0-2.2 (m, 2 H), 2.4 (q, 2 H, J=7 Hz), 2.6-2.8 (m, 4 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.6 (br cl, 1 H, J=7 Hz), 3.85 (q, 2 H, J=7Hz), 4.75 (br s,2 H), 5.2 (d, 1 H, J=7Hz), 5.75 (d, 1 H, J=10Hz), 6.2 (q, 2 H, J=7 Hz), 7.15 (s, 1 H), 9.15 (s, 1 H); mass spectrum m/z 600 (M+); Analysis calculated for C31 H44 N4 O8 : C, 61.98; H, 7.38; N, 9.33%. Found: C, 61.30; H, 7.31; N, 9.12%.
PAC 17-Azetidin-1-yl-5-dihydro-17-demethoxyceldanamycinMp 110°C (foam); 1 H-NMR (300 MHz, CDCl3)δ0.95 (d, 3 H, J=7 Hz), 1.0 (d, 3 H, J=7 Hz), 1.7 (s, 3 H), 1.6-1.8 (m, 9 H), 1.9 (s, 3 H), 2.2 (d, 1 H, J=14 Hz, 7 Hz), 2.3-2.55 (m, 4 H), 2.65 (d, 1 H, J=14 Hz), 2.75 (m, 1 H), 3.35 (m, 1 H), 3.38 (s, 3 H), 3.4 (s, 3 H), 3.5 (m, 1 H), 3.6 (d, 1 H, J=10 Hz), 4.5-4.8 (m, 6 H), 5.2 (d, 1 H, J=7 Hz), 5.7 (d, 1 H, J=10 Hz), 6.25 (t, 1 H, J=10 Hz), 7.0 (s, 1 H), 9.3 (br s, 1 H); mass spectrum m/z 587 (M+).
PAC 17-(3'-Hydroxyazetidin-1-yl)-4,5-dihydro-17-demethoxygeldanamycinMp (amorphous); 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H), 1.5-1.8 (m, contains 1 methyl singlet, 8 H), 1.9 (s, 3 H), 2.2 (m, 1 H), 2.35 (m, 2 H), 2.6 (br d, 1 H, J=14 Hz), 2.75 (m, 1 H), 3.2-3.5 (m, contains 2 methyl singlets, 8 H), 3.6 (d, 1 H, J=10 Hz), 4.3-4.6 (m, 2 H), 4.7 (m, 1 H), 4.75-5.0 (m, 4 H), 5.15 (d, 1 H, J=4 Hz), 5.8 (d, 1 H, J=10 Hz), 6.2 (br t, 1 H, J=7 Hz), 6.95 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 626 (M+Na); Analysis calculated for C31 H45 N3 : C, 61.68; H, 7.51; M, 6.96%. Found: C, 61.21; H, 7.51; N, 6.75%.
PAC 17-(3'-Methoxyazetidin-1-yl)-4,5-dihydro-17-demethoxygedanamycinMp 118°C (foam); 1 H-NMR (300 MHz, CDCl3)δ1.0 (m, 6 H, two methyl doublets), 1.5-1.8 (m, 8 H, contains methyl singlet), 1.9 (s, 3 H), 2.0-2.3 (m, 1 H), 2.4 (m, 2 H), 2.5-2.8 (m, 2 H), 3.2-3.5 (m, 11 H, contains 3 methyl singlets), 3.6 (m, 1 H), 4.0 (d, 1 H, J=7 Hz), 4.2 (m, 1 H), 4.34.6 (m, 2 H), 4.64.9 (m, 4 H), 5.2 (d, 1 H, J=4 Hz), 5.8 (d, 1 H, J=10 Hz), 6.25 (br t, 1 H, J=7 Hz), 7.0 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 640 (M+ +Na); Analysis calculated for C32 H47 N3 O9.H2 O: C, 60.84; H, 7.18; N, 6.65%. Found: C, 60.74; H, 7.54; N, 6.75%.
PAC 17-Azetidin-1-yl-4,5-dihydro-11-α-fluoro-17-demethoxygeldanamycinA solution of diethylaminosulfurtrifluoride (DAST) (0.154 g, 0.960 mmol, 0.127 mL) in 3 mL of methylene chloride was added to a flame dried flask under nitrogen and cooled to -68°C with an external dry ice/acetone bath. 17-Azetidine-1-yl-4,5-dihydro-17-demethoxygeldanamycin (0.188 g, 0.320 mmol) dissolved in 15 mL of methylene chloride was added dropwise. After 0.5 hour 5 mL of 5% aqueous NaHCO3 was added slowly at about -68°C After warming to room temperature the product was extracted into 100 mL of methylene chloride. The organic layer was washed with 3×50 mL of water and 2×50 mL of brine, dried with MgSO4, filtered and concentrated to a purple solid which was purified by flash column chromatography using 5:95 methanolhloroform. Material of Rf=0.42 (1:9 methanol:chlciroform), the desired product was disolved in a minimal amount of ethyl acetate and precipitated with hexanes; Yield 0.096 9 (51%), mp 104°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.00(d, J=8 Hz, 3H, 14-CH3), 1.06(d, J=8 Hz, 3H, 10-CH3), 1.4 (br m, 2H, H-13),1.56 (s, 3H, 8-CH3), 1.75 (m, 1H, H-14), 1.89 (s, 3H, 2-CH3), 2.20 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.4 (br m, 3H, 3' azetidine CH2 and H-5), 2.66 (dd, J=7 Hz, 16 Hz, 1 H, H-15), 2.75 (br d, J=26 Hz, 1H, H-10), 3.25 (m, 1H, H4), 3.4 (br s, 7H, 6-OCH3, 12-OCH3 and H-4), 3.60 (br m, 1 H, H-12), 4.40 (br d, J=44 Hz, 1 H, H-11), 4.65 (br m, 7H, NH2 and 2' and 4' azetidine CH2 and H-6), 5.06 (d, J=8 Hz, 1H, H-7), 5.62 (d, J=9 Hz, 1H, H-9), 6.13 (br t, 1H, H-3), 6.96 (s, 1H, H-19), 9.27 (s, 1H, NH-22); m/z 612. (M++Na); IR (KBr, cm-1) 1735, 1695, 1650; Analysis calculated for C31 H44 FN3 O7∅25H2 O: C, 62.66; H, 7.96; N, 7.07%. Found: C, 62.38; H, 7.53; N, 6.97%.
PAC 17-Allylamino-4,5-dihydro-11-α-fluoro-17-demethoxygeldanamycinThe title compound was made by the method of Example 15 from 17-allylamino-4,5-dihydro-17-demethoxygeldanamycin. Yield 0.079 g (44%), mp 84°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.02(d, 3H, J=8Hz, 14-CH3), 1.07(d, 3H, J=8Hz, 10-CH3), 1.45 (br m, 2H, H-13), 1.60 (s, 3H, 8-CH3), 1.7 (m, 2H, H-5), 1.83 (br m, 1H, H-14), 1.90 (s, 3H, 2-CH3), 2.30 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.4 (m, 2H, H-4), 2.70 (dd, J=7 Hz, 16 Hz,1 H, H-15), 2.75 (br d, J=26 Hz,1 H, H-10), 3.26 (m,1 H, H-6), 3.40 and 3.43 (br s, 6H, OCH3), 3.57 (br m, 1 H, H-1 2), 4.08 (br t, 2H, allylic CH2), 4.35 (br d, J=47 Hz, 1 H, H-11), 4.65 (br m, 2H, NH2), 5.07 (s, 1H, H-7), 5.25 (br d, 2H, vinylic CH2), 5.61 (d, J=9 Hz, 1H, H-9), 5.9 (m, 2H, H-5 and vinylic CH), 6.15 (br t, 1H, H-3), 6.32 (br t, 1H, NH), 7.15 (s, 1H, H-19), 9.25 (s, 1H, NH-22); m/z 612. (M++Na); IR (KBr, cm-1) 1730,1695,1655; Analysis calculated for C31 H4 FN3 O7 0.25H2 O: C, 62.66; H, 7.96; N, 7.07%. Found: C, 62.53; H, 7.32; N, 6.97%.
PAC 17-Azetidin-1-yl-4,5-dihydro-11-keto-17-demethoxygeldanamycinPrepared from 17-azetidin-1-yl4,5-dihydro-17-demethoxygeldanamycin by the method of Example 76; 1 H-NMR (300 MHz, CDCl3)δ1.0 (d, 3 H, J=6), 1.3 (d, 3 H, J=6), 1.35-1.5 (m, 2 H), 1.5-1.8 (m, 6 H, contains methyl singlet), 1.9 (s, 3 H), 2.15-2.3 (m, 2 H), 2.45-2.5 (m, 2 H), 2.6 (m, 1 H), 3.15 (m, 1 H), 3.35 (s, 3 H), 3.4 (s, 3 H), 3.55 (m, 1 H), 4.0 (m, 1 H), 4.65 (m, 4 H), 4.8 (br s, 2 H), 5.0 (d, 1 H, J=6 Hz), 5.55 (d, 1 H, J=8 Hz), 6.25 (m, 1 H), 6.92 (s, 1 H), 9.2 (s, 1H); mass spectrum m/z 608 (M+Na);
PAC 17-Azetidin-1-yl-17-demethoxygeldanamycinGeldanamycin (14.0 gm, 25.0 mmol) was added to a flame dried flask under nitrogen and slurried in 350 mL of methylene chloride. Azetidine (2.85g, 49.9 mmol, 3.36 mL) in 10 mL of methylene chloride was added dropwise. The yellow suspension turned purple during the addition. After 1 hour the reaction mixture was evaporated to dryness and the residue dissolved in 50 mL of chloroform and precipitated with 600 mL of hexanes. Filtration and vacuum drying at 70°C afforded pure product, yield 14.2 gm (97%); 225 C; 1 H-NMR (300 MHz, CDCl3)δ0.94 (br t, 6H, 10-CH3 and 14-CH3), 1.2 (m, 1H, H-13), 1.65 (m, 1H, H-13), 1.73 (m, 1H, H-14), 1.76 (s, 3H, 8-CH3), 2.0 (s, 3H, 2-CH3), 2.17 (dd, J=12 Hz, 16 Hz, 1H, H-15), 2.40 (p, J=8 Hz, 2H, 3' azetidine CH2), 2.56 (d, J=16 Hz, 1H, H-15), 2.67 (m, 1H, H-10), 3.20(s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.40 (m, 1H, H-12), 3.50 (m, 1H, H-11), 4.25 (d, J=10.5 Hz, 1H, H-6), 4.54.9 (m, 6H, 2' and 4' azetidine CH2 and NH2), 5.13 (s, 1H, H-7), 5.79 (t, J=9 Hz, 1H, H-5), 5.87 (d, J=9 Hz, 1H, H-9), 6.53 (t, J=9 Hz, 1H, H-4), 6.88 (d, J=9 Hz, 1H, H-3), 7.06 (s, 1H, H-19), 9.13 (s, 1H, NH-22); m/z 608. (M++Na); IR (KBr, cm -1) 1730, 1680, 1645; Analysis calculated for C31, H43 N3 O8 : C,63.54; H, 7.40; N, 7.17%; Found: C, 63.09; H, 7.33; N, 6.85%.
PAC 17-Propargylamino-17-demethoxygeldanamycinPropargylamine hydrochloride (0.200 gm, 2.180 mmol) and triethylamine (0.2206 gm, 2.180 mmol, 0.303 mL) were added to a flame dried flask under nitrogen and slurried in 5 mL chloroform. After 10 minutes geldanamycin (0.200 gm, 0.3567 mmol) was added to the mixture and the reaction was stirred at room temperature overnight. The solution changed from a pale yellow color to a dark orange/red color. The reaction mixture was diluted with 50 mL chloroform and washed with 3×25 mL 1N hydrochloric acid. The organic layer was then dried over magnesium sulfate, fill ered and evaporated to dryness to yield a crude purple residue. The crude product was then purified by flash column chromotography using 200 gm silica gel and eluting with 3:97 isopropyl alcohol:methylene chloride to afford pure purple product, 0.015 gm (7%) mp 172°C; 1 H-NMR (300 MHz, CDCl3)δ0.96-1.10 (m, 1H, H-13), 1.00 (d, J=8 Hz, 3H, 1-CH3), 1.01 (d, J=8 Hz, 3H, 14-CH3), 1.62-1.90 (br m, 2H, H-13, H-14), 1.76 (s, 3H, 8-CH3), 2.04 (s, 3H, 2-CH3), 2.34-2.47 (br m, 1H, H-1 5), 2.42 (s, 1H, acelylene CH), 2.68-2.81 (br m, 2H, H-10, H-15), 3.28 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 3.49 (br m, 1H, H-12), 3.61 (br m, 1H, H-11), 4.02 (d, J=6 Hz, 1H, H-6), 4.31 (s, 1H, 11-OH), 4.32 (m, 2H, propargyl CH2), 4.77 (br m, 2H, NH2), 5.21 (s, 1H, H-7), 5.87 (t, J=9 Hz, 1 H, H-5), 5.90 (d, J=9 Hz, 1H, H-9), 6.32 (br t, 1H, NH), 6.60 (t, J=9 Hz, 1H, H-4), 6.97 (d, J =9 Hz, 1H, H-3), 7.32 (s, 1H, H-19), 9.09 (s, 1H, NH-22); m/z 606.3 (M++Na); IR (KBr, cm -1) 2120, 1730, 1695, 1645; Analysis calculated for C31 H41 N3 O8.3.50H2 O: C, 57.55; H, 7.47; N, 6.49%. Found: C, 57.55; H, 6.14; N, 6.23%.
PAC 17-(2'-Cyanoethylamino)-17-demethoxygeldanamycinGeldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under nitrogen and slurried in 5 mL chloroform. 3-Aminopropionitrile 0.153 gm (2.18 mmol, 0.161 mL) was added and the reaction mixture was stirred att room temperature overnight. The reaction mixture went from a pale yellow color to a dark red/orange color. An additional 0.161 mL of 3-aminopropionitrile was added and the reaction mixture was refluxed for 8 hours. The cooled reaction mixture was diluted with 75 mL chloroform and washed with 3×50 mL water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The purple residue was recrystallized from a minimal amount of hot ethyl acetate affording pure purple product, 0.160 gm (75%) mp 152°C; 1 H-NMR (300 MHz, CDCl3)δ0.74-0.91 (br m, 1H, H-13), 0.82 (d, J=7 Hz, 3H, 10-CH3) 0.82 (d, J=7 Hz, 3H, 14-CH3), 1.45-1.7 (br m, 2H, H-13, H-14),1.61 (s, 3H, 8-CH3),1.83 (s, 3H, 2-CH3), 1.93-2.09 (br m, 1H, H-15), 2.49-2.64 (m, 4H, β-ethyl CH2, H-10, H-15), 3.08 (s, 3H, OCH3), 3.19(s, 3H, OCH3), 3.28 (br m, 1H, H-12), 3.39 (m, 1H, 11-H), 3.62-3.79 (br m, 2H, α-ethyl CH2), 4.12 (d, J=9 Hz, 1H, H-6), 4.62 (br m, 2H, NH2), 5.00 (s, 1 H, H-7), 5.62-5.72 (br m, 2H, H-5, H-9), 5.96 (br t, 1 H, NH), 6.40 (t, J=9 Hz, 1H, H-4), 6.78 (d, J=9 Hz, 1H, H-3), 7.12 (s, 1H, H-19), 8.82 (s, 1H, NH-22); m/z 621.3 (M++Na); IR (KBr, cm-1) 1730, 1690, 1650, 1585, 1480; Analysis calculated for C31 H42 N4 O8 : C, 62.19; H, 7.07; N, 9.35%. Found: C, 62.02; H, 6.63; N, 9.09%.
PAC 17-(2'-Fluoroethylamino)-17-demethoxygeldanamycin17-(2'-Fluoroethylamino)-17-demethoxygeldanamycin was prepared by the method of Example 19. Pure purple product was obtained from the crude residue after flash column chromatography using 200 gm silica gel eluting with 20% acetone in methylene chloride; yield 0.060 gm (28%) mp 176°C; 1 H-NMR (300 MHz, CDCl3)δ0.87 (d, J=7 Hz, 3H, 10-CH3), 0.91 (d, J=7 Hz, 3H, 14-CH3), 1.55-1.73 (br m, 3H, H-13, H-14), 1.70 (s, 3H, 8-CH3), 1.92 (s, 3H, 2-CH3), 2.21 (dd, J=8 H;z, 16 Hz, 1H, H-15), 2.62 (br m, 2H, H-10, H-15), 3.14 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.35 (br m, 1H, H-12), 3.48 (br m, 1H, H-11), 3.59-3.91 (br m, 2H, α-ethyl CH2), 4.19 (d, J=9 Hz, 1H, H-6), 4.65 (two br t, J=46 Hz, 5 Hz, 2H, β-ethyl CH2), 4.52-4.79 (br m, 2H, NH2), 5.07 (s, 1 H, H-7), 5.72 (br m, 2H, H-5,H-9), 6.29 (br t, 1 H, NH), 6.48 (t, J=9 Hz, 1 H, H-4), 6.85 (d, J=9 Hz, 1H, H-3), 7.14 (s, 1H, H-19), 8.97 (s, 1H, NH-22); m/z 591.3. (M+); IR (KBr, cm-1) 1742, 1655, 1585; Analysis calculated for C30 H42 N3 O8 : C, 60.90; H, 7.15; N, 7.10%. Found: C, 60.65; H, 6.90; N, 6.92%.
PAC 17-tert-Butylamino-17-demethoxy-geldanamycinGeldanamycin (0.200 gm, 0.3567 mmol) was slurried in 5 mL of tert-butylamine, in a flame dried flask under nitrogen, at reflux overnight. The reaction color went from yellow to dark purple. The reaction mixture was evaporated to dryness. The residue was dissolved into 50 mL chloroform. The chloroform s;olution was washed with 3×25 mL brine and 3×25 mL water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromotagraphy with 200 gm silica gel eluted with 10% acetone/methylene chloride; yield 0.053 gm (25%) mp 102°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.89 (d, J=5 Hz, 3H, 10-CH3), 0.94 (d, J=5 Hz, 3H, 14-CH3), 1.39 (s, 9H, t-butyl CH3), 1.49-1.80 (br m, 3H, H-13, H-14), 1.74 (s, 3H, 8-CH3), 1.98 (s, 3H, 2-CH3), 2.27 (br m, 1H, H-15), 2.65 (br m, 2H, H-10, H-15), 3.21 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.99 (br m, 1H, H-12), 3.45 (br m, 1H, H-11), 4.17 (br m, 1H, 11-OH), 4.23 (d, J=7 Hz, 1H, H-6), 4.72-4.91 (br m, 2H, NH2), 5.13 (s, 1H, H-7), 5.82 (br m, 3H, H-5, H-9, NH), 6.51 (t, J=7 Hz, 1H, H-4), 6.87 (d, J=7 Hz, 1H, H-3), 7.18 (s, 1H, H-19), 8.96 (s, 1H, NH-22); m/z 601.4 (M+); 1R (KBr, cm-1) 1720, 1685, 1645, 1585, 1560; Analysis calculated for C32 H47 N3 O8 : C, 63.87; H, 7.87; N, 6.98%. Found: C, 63.91; H, 7.95; N, 6.03%.
PAC 17-(2'-Mercaptoethylamino)-17-demethoxygeldanamycinGeldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under nitrogen and slurried in 5 mL pyridine. Thiazolidine (0.194 gm, 2.18 mmol, 0.171 mL) was added and the reaction mixture was heated at 70°C for 2 hours. The reaction mixture was evaporated to dryness in vacuo. The crude product was purified by flash column chromatography using 200 gm silica gel eluting with -4% methanol in methylene chloride to afford pure purple product, 0.041gm (20%) mp 156°C; 1 H-NMR (300 MHz, CDCl3)δ0.99 (d, J=5 Hz, 6H, 10-CH3,14-CH3),1.63-1.81 (br m, 3H, H-1 3, H-14), 1.78 (s, 3H, 8-CH3), 2.01 (s, 3H, 2-CH3), 2.47(m, 1 H, H-15), 2.64-2.79 (br m, 2H, H-10, H-15), 2.83-3.00 (br m, 2H, 2'-CH2), 3.25 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.42 (m, 1H, H-12), 3.55 (m, 1H, H-11), 3.87 (m, 2H, 1'-CH2), 4.10 (br m, 1H, 11-CH), 4.29 (d, J=9 Hz, 1H, H-6), 4.92 (br m, 2H, NH2), 5.16 (s, 1 H, H-7), 5.81-5.89 (br m, 2H, H-5, H-9), 6.48 (br t, 1H, NH), 6.55 (t, J=9 Hz, 1 H, H-4), 6.94 (d, J=9 Hz, 1H, H-3), 7.24 (s, 1 H, H-19), 9.12(s, 1H, NH-22); m/z 642.3(M++Na); IR (CHCl3, cm-1) 1730, 1690, 1655, 1575; Analysis calculated for C30 H44 N3 O8 S.H2 O; C, 57.67; H,7.41; N, 6.72%. Found: C, 57.44; H, 6.37; N, 6.72%.
PAC 17-[2'Methylthio)ethylaminol]-17-demethoxygeldanamycinGeldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under nitrogen and slurried in 5 mL chloroform. 2-(Methylthioethylamine (0.199 gm, 2.18 mmol,) was added and the reaction was stirred at room temperature for 36 hours. The reaction mixture was diluted with 75 mL chloroform and washed with 2×50 mL 1N hydrochloric acid, 2×50 mL brine and 3×50 mL water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by flash column chromatography using 200 gm silica gel and eluting with 3% acetonitrile in ethyl ether to afford pure purple product, 0.095gm (43%) mp 157°C; 1 H-NMR (300 MHz, CDCl3)δ1.09(d, J=7 Hz, 3H, 14-CH3), 1.14 (d, J=7 Hz, 3H, 10-CH3), 1.71-1.89 (br m, 3H, H-13, H-14), 1.89 (s, 3H, 8-CH3), 2.13 (s, 3H, 2-CH3), 2.22 (s, 3H, SCH3), 2.46 (dd, J=7Hz, 13Hz, 1H, H-15), 2.79 (d, J=13 Hz, 1H, H-15), 2.72-2.92 (br m, 3H, 2'-CH2, H-10), 3.36 (s, 3H, OCH3), 3.46 (s, 3H, OCH3), 3.54 (m, 1H, H-12), 3.68 (t, J=7 Hz, 1H, H-11), 3.72-3.86 (br m, 1H, 1'CH2), 3.86-3.95 (br m, 1H, 1'CH2), 4.41 (d, J=7 Hz, 2H, H-6, 11-OH), 4.93(br m, 2H, NH2), 5.28 (s, 1 H, H-7), 5.91-6.04 (br m, 2H, H-5, H-9), 6.62-6.74 (br m, 2H, H-4, NH), 7.03(d, J=7 Hz, 1 H, H-3), 7.37 (s, 1 H, H-19), 9.22 (s, 1 H, NH-22); m/z 642.3 (M++Na); I (CHCl3, cm -1) 1735, 1685, 1650, 1570; Analysis calculated for C31 H45 N3 O8 S.1.5H2 O: C, 57.56; H, 7.48; N, 6.49%. Found: C, 57.30; H, 6.87; N, 6.21%.
PAC 17-[(S)-2'-Azetidinecarboxylicacid]-17-demethoxygeldanamrycinGeldanamycin (0.200 gm, 0.3567 mmol) was added to a flame dried flask under nitrogen and slurried in 5 mL chloroform. (S)-2-Azetidine carboxylic acid (0.200 gm, 1.978 mmol) in 2 mL of pyridine, and triethylamine (0.200 gm, 1.978 mmol, 0.275 mL) were added. The reaction mixture was stirred at room temperature for 36 hours, refluxed for 4 hours, cooled to room temperature, diluted with 75 mL chloroform and washed with 2×50 mL 1N hydrochloric acid. The organic layer was extracted with 3×50 mL 1N NaOH. The pooled basic phases were acidified to pH═6 with 1N hydrochloric acid and extracted with 3×75 mL chloroform. The combined chloroform layers were dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was dissolved in a minimal amount of ethyl acetate and precipitated with hexane to afford pure purple product, 0.056 gm (25%) mp 2,0°C (dec); 1 H-NMR (C5 D5 N)δ1.29-1.47 (br m, 6H, 10-CH3, 14-CH3), 1.94-2.22(br m, 3H, H-13, H-14), 2.09 (s, 3H, 8-CH3), 2.23 (s, 3H, 2-CH3), 2.49 (br m, 1H, H-15), 2.81 (t, J=7 Hz, 1 H, H-10), 2.99 (br m, 1H, 4'azetidine-CH), 3.28(br m, 1H, 4'azetidine-CH), 3.42 (s, 3H, OCH3), 3.50 (s, 3H, OCH3) 3.81 (m, 1H, H-12), 4.14 (m, 1H, H-11), 4.34 (br m, 1H, 3'azetidine-CH), 4.89 (br m, 1H, 3'azetidine-CH), 5.01 (d, J=7 Hz, 1H, H-6), 5.73 (m, 1H, 2'azetidine-CH), 5.91 (s, 1H, H-7 ), 6.21 (t, J=7 Hz, 1H, H-5), 6.47 (d, J=7 Hz, 1H, H-9), 6.60 (t, J=7 Hz, 1 H, H-4), 7.41-7.54 (br m, 2H, H-3, H-19), 9.57 (s, 1 H, NH-22); m/z 652.3 (M++Na); IR (CHCl3, cm-1) 1730, 1695, 1645, 1585; Analysis calculated for C32 H43 N3 O10.3H2 O: C, 56.21; H, 7.22; N, 6.14%. Found: C, 56.16; H, 6.13; N, 6.04%.
The compounds of Examples 26-31 were prepared from geldanamycin and the appropriate amines by the method of Example 1 above.
PAC 17-Histamino-17-demethoxygeldanamycinMp 150°C (decomp); 1 H-NMR (300 MHz, CDCl3)δ0.98 (overlapping d, 6 H), 1.68 (m, 1 H), 1.77 (s, 3 H), 2.02 (s, 3 H), 2.43 (t, 1 H, J=7 Hz), 2.6-2.8 (m, 2 H), 2.94 (t, 2H, J=5 Hz), 3.23 (s, 3 H), 3.39 (s, 3 H), 3.40 (m, 1 H), 3.52 (m, 1 H), 3.7-3.9 (m, 2 H), 4.27 (d, 1 H, J=9 Hz), 4.88 (br exchangeable, 2 H), 5.13 (s, 1 H), 5.85 (m, 2 H), 6.56 (t, 1 H, J=12 Hz), 6.75 (m, 1 H), 6.92 (m, 2 H), 7.19 (s, 1 H), 7.61 (s, 1 H), 9.17 (s, 1 H); mass spectrum m/z 640 (M+); Analysis calculated for C35 H45 N5 O8. 0.5(ethyl acetate): C, 61.48; H, 7.22; N, 10.24%. Found: C, 61.06; H, 7.3; N, 10.32%.
PAC 17-Furfurylamino-17-demethoxygeldanamycinMp 122-130°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.09 (overlapping d, 6 H), 1.75 (m, 1 H), 1.79 (s, 3 H), 1.98 (s, 3 H), 2.42 (dd, 1 H, J=7Hz, 6Hz), 2.72 (m, 2 H), 3.28 (s, 3 H), 3.37 (s, 3 H), 3.48 (m, 1 H), 3.59 (m, 1 H), 4.18 (br exchangeable, 1 H), 4.29 (d, 1 H, J=9 Hz), 4.67 (dd, 1 H, J=9 Hz, 5 Hz), 4.73 (dd, 1H, J=9 Hz, 5 Hz), 4.88 (br exchangeable, 2 H), 5.18 (s, 1 H), 5.89 (m, 2 H), 6.28 (m, 1 H), 6.34 (m, 1 H), 6.42 (m, 1 H), 6.57 (t, 1 H, J=12 Hz), 6.94 (d, 1 H, J=12 Hz), 7.28 (s, 1 H), 7.41 (s, 1 H), 9.11 (s, 1 H); mass spectrum m/z 626 (M+); Anailysis calculated for C33 H43 N3 O9∅33CHCl3 : C, 62.31; H, 6.90; N, 6.54%. Found: C, 62.28; H, 6.78; N, 6.63%.
PAC 17-Tetrahydrofurfurylamino-17-demethoxygeldanamycinMp 157-166°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.05 (overlapping d, 6 H), 1.7 (m, 2 H), 1.87 (s, 3 H), 1.9-2.1 (m, 3 H), 2.05 (s, 3 H), 2.38 (m, 1 H), 2.70 (m, 2 H), 3.27 (s, 3 H), 3.34 (s, 3 H), 3.45 (m, 1 H), 3.53 (m, 2 H), 3.82 (m, 1 H), 3.93 (m, 1 H), 4.09 (m, 1 H), 4.27 (d, 1 H, J=8 Hz), 4.88 (br exhangeable, 2 H), 5.18 (s, 1 H), 5.7-6.0 (m, 2 H), 6.56 (m, 2 H), 6.93 (d, 1 H, J=11 Hz), 7.26 (s, 1 H), 9.17 (s, 1 H); mass spectrum m/z 632 (M++2); Analysis calculated for C33 H47 N3 O9 : C, 62.94; H, 7.52; N, 6.69%. Found: C, 62.92; H, 7.57; N, 6.39%.
PAC 17-Tetramethylguanidino-17-demethoxygeldanamycinMp 140-145°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.0 (overlapping d, 6 H), 1.70 (m, 1 H), 1.77 (s, 3 H), 2.02 (s, 3 H), 2.51 (m, 2 H), 2.76 (br s, 6 H), 2.83 (s, 6 H), 3.26 (s, 3 H), 3.38 (s, 3 H), 3.42 (m, 1 H), 3.60 (m, 1 H), 4.28 (d, 1 H, J=9 Hz), 5.15 (s, 1 H), 5.83 (t, 1 H, J=7Hz), 5.95 (m, 1 H), 6.57 (t, 1 H, J=12Hz), 6.97 (br d, 1 H, J=12 Hz), 7.07 (s, 1 H), 9.36 (br s, 1 H); mass spectrum m/z 646 (M +2); Analysis calculated for C33 H49 N5 O8∅2CHCl3 : C, 60.55; H, 7.56; N, 10.64%. Found: C, 60.57; H, 7.67; N, 10.59%.
PAC 17-betα-Alanyl-17-demethoxygeldanamycinMp 143-147°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.99 (overlapping d, 6 H), 1.67 (m, 1 H), 1.79 (s, 3 H), 2.03 (s, 3 H), 2.32 (m, 1 H), 2.69 (m, 3 H), 3.22 (s, 3 H), 3.32 (s, 3 H), 3.42 (m, 1 H), 3.55 (m, 1 H), 3.82 (m, 2 H), 4.28 (d, 1 H, J=9), 5.08 (br s, 2 H), 5.19 (s, 1 H), 5.83 (m, 2 H), 6.58 (m, 2 H), 6.91 (d, 1 H, J=12 Hz), 7.25 (s, 1 H), 9.09 (s, 1 H); mass spectrum m/z 640 (M+Na); Ana.lysis calculated for C31 H43 N3 O10.H2 O: C, 58.66; H, 6.99; N, 6.62%. Found: C, 58.98; H, 7.03; N, 6.60%.
PAC 17-Homohistamino-17-demethoxygeldanamycinMp 128-136°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.87 (d, 3 H, J=7 Hz), 0.98 (d, 3 H, J=7 Hz), 1.7 (m, 3 H), 1.76 (s, 3 H), 1.98 (s, 3 H), 2.12 (m, 4 H), 2.5-2.7 (m, 3 H), 3.21 (s, 3 H), 3.32 (s, 3 H), 3.4-3.55 (m, 4 H), 4.05 (m, 2 H), 4.27 (d, 1 H, J=9 Hz), 4.85 (br exchangeable, 2 H), 5.13 (s, 1 H), 5.85 (m, 2 H), 6.22 (m, 1 H), 6.57 (t, 1 H, J=11 Hz), 6.88 (m, 2 H), 7.08 (s, 1 H), 7.26 (s, 1 H), 7.53 (s, 1 H), 9.09 (s, 1 H); mass spectrum m/z 654 (M +1); Analysis calculated for C34 H47 N5 O8∅1CH2 Cl2 : C, 61.84; H, 7.18; N, 10.57%. Found: C, 61.90; H, 7.49; N, 10.29%.
PAC 17-Amino-22-(4'-fluorophenacyl)-17-demethoxygeldanamycin17-Amino-17-demethoxygeldanamycin (0.254 g, 0.465 mmol) was dissolved in 5 mL anhydrous dimethyl sulfoxide in flame dried glassware. Potassium t-butoxide (0.054 9, 0.468 mmol) was added and the solution stirred at room temperature under nitrogen for 30 minutes. p-Fluorophenacyl bromide (0.102 g, 0.479 mmol) was added and the solution stirred at room temperature for 1.5 hours. This solution was diluted with ethyl acetate, washed with water and brine, dried over magniesium sulfate, filtered and evaporated in vacuo. The resulting purple residue was flash chromatographed with silica gel eluted with 2% methanol in chloroform to give a purples solid; Yield 0.270 g (66%): mp 183-185°C(dec); 1 H-NMR (300 MHz, CDCl3)δ0.61 (br s , J=7 Hz, 3H, 14-CH3), 0.78 (br m, 1 H, H-13), 0.93 (d, J=7 Hz, 3H, 10-CH3), 1.30(s, 3H, 8-CH3), 1.49 (br m, 1H, H-13), 1.82 (dd, J=15 Hz and 4 Hz, 1H, H-15), 1.92 (s, 3H, 2-CH3), 2.02 (br s, 1H, 11-OH), 2.20 (br m, 2H, H-10 and H-14), 2.77 (dd, J=15 Hz and 4 Hz, 1H, H-15), 2.84 (br d, J=10 Hz, 1 H, H-12), 3.23 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.54 (d, J=9 Hz, 1H, H-11), 4.19 (t, J=9 Hz, 1H, H-6), 4.41 (d, J=16 Hz, 1H, α-CH2), 4.95 (d, J=9 Hz, 1H, H-7), 4.97 (s, 2H, NH2), 5.12 (d, J=8 Hz, lH, H-9), 5.20 (t, J=9 Hz, 1 H, H-5), 5.40 (br s, 2H, NH2), 5.84 (s, 1 H, H-19), 5.96 (d, J=17 Hz, 1 H, α-CH2), 6.35 (t, J=10 Hz, 1H, H-4), 7.03 (d, J=13 Hz, 1H, H-3), 7.12 (m, 2H, aromatic), 7.99 (m, 2H, aromatic); m/z 704 (M++Na); IR (KBr, cm-1) 1722, 1691, 1675, 1659, 1580, 1504; Anal. for C3,H44 N3 O9 F: C, 63.42; H, 6.51; N, 6.16%. Found C, 63.40; H, 6.65; N, 5.84%.
The compounds of Examples 33 to 45 were prepared by thie method of Example from the appropriately substituted phenacyl bromides.
PAC 17-Amino-22-(2',4'-dimethylphenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was purified by Chromatotron (trademark) using 2% methanol in chloroform and again with 1% methanol in chloroform to give fractions containing essentially pure product which were evaporated in vacuo to yield a red solid which was further purified by preparative HPLC using a Zorbax (trademark) column eluted with 54:1:45 ethyl acetate:methanol:hexanes. Fractions containing pure material were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; Yield 0.002 gm, (0.6%) mp 154°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.55 (d, J=6 Hz, 3H, 14-CH3), 0.89 (d, J=6 Hz, 3H, 10-CH3), 2.76 (m, 2H, H-10, H-15), 3.04-3.19 (m, 1H, H-12), 3.11 (s, 3H, OCH3), 3.17 (s, 3H, OCH3), 3.47 (m, 1H, H-11), 4.12(t, J=7 Hz, 1H, H-6), 4.21 (d, J=15 Hz, 1H, α-CH), 4.43(br s, 2H, NH2), 4.83 (d, J=7 Hz, 1H, H-7), 4.89-5,07 (m, 2H, NH2), 5.04(d, J=7 Hz, 1H, H-9), 5.10(t, J=7 Hz, 1 H, H-5), 5.71 (d, J=15 Hz, 1 H, α-CH), 5.80(s, 1 H, H-1 9),6.22(t, J=7 Hz, 1H, H-4), 6.81-7.03(m, 3H, H-3, Aromatic), 7.5 (d, J=7 Hz, 1H, Aromatic). m/z 714 (M++Na); IR (KBr, cm-1) 1720, 1670, 1655, 1580; Analysis calculated for C38 H49 N3 O9∅5H2 O:C, 65.12; H, 7.19; N, 6.07%. Found C, 55.3H, 6.89; N, 5.99%.
PAC 17-Amino-22-(2'-methoxyphenacyl)-17-demethoxygeldanamycinYield 0.110 g (34%): mp 165-168°C; 1 H-NMR (300 MHz, CDCl3)δ0.72 (d, J=7 Hz, 3H, 14-CH3), 0.84 (m, 1H, H-13), 1.03 (d, J=7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.49 (m,1 H, H-13), 1.90 (dd, J=12 Hz and 4 Hz,1 H, H-15), 2.03 (s, 3H, 2-CH3), 2.24 (br m, 2H, H-10 and H-14), 2.41 (s,1H, 11-OH), 2.94 (m, 2H, H-12 and H-15), 3.30 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.62 (d, J=8 Hz, 1H, H-11), 3.97 (s, 3H, OCH3), 4.28 (t, J=10 Hz, 1H, H-6), 4.51 (d, J=19 Hz, 1H, α-CH2), 4.60 (br s, 2H, NH2), 5.02 (d, J=10 Hz, 1 H, H-7), 5.10 (br s, 2H, NH2), 5.20 (d, J=9 Hz, 1 H, H-9), 5.27 (t, J=12 Hz, 1H, H-5), 5.86 (d, J=17 Hz, 1H, α-CH2), 5.98 (s, 1H, H-19), 6.40 (t, J=13 Hz, 1H, H-4), 7.03 (m, 2H, aromatic), 7.14(d, J=12 Hz, 1H, H-3), 7.56 (m, 1H, aromatic), 7.90 (m, 1H, aromatic); m/z 694 (M+); IR (KBr, cm-1) 1732, 1678, 1661, 1584.
PAC 17-Amino-22-(3'-methoxyphenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was dissolved in 1 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 151 g (48%): mp 165-168°C; 1 H-NMR (300 MHz, CDCl3) 6 0.67 (Cl, J=9 Hz, 3H, 14-H3), 0.78 (m, 1H, H-13), 0.98 (d, J=9 Hz, 3H, 10-CH3),1.32 (s, 3H, 8-CH3), 1.43 (m, 1H, H-13), 1.83 (dd, J=15 Hz and 5 Hz, 1H, H-15), 1.92 (s, 3H, 2-CH3), 2.10-2.27 (br m, 2H, H-10 and H-14), 2.42 (s,1 H, 11-OH), 2.82-2.89 (m, 2H, H-2 and H-15), 3.22 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.58 (d, J=11 Hz, 1H, H-11), 3.81 (s, 3H, OCH3), 4.22 (t, J=10 Hz, 1H, H-6), 4.40 (d, J=18 Hz, 1H, α-CH2), 4.68 (br s, 2H, NH2), 4.99 (d, J=9 Hz, 1 H, H-7), 5.15 (br s, 2H, NH2), 5.16 (d, J=11 Hz, 1 H, H-9), 5.21 (t, J=11 Hz, 1H, H-5), 5.90 (s, 1H, H-19), 5.97 (d, J=17 Hz, 1H, α-CH2), 6.35 (t, J=12 Hz, 1H, H-4), 7.02 (d, J=11 Hz,1 H, H-3), 7.12 (dd, J=8 Hz and 5 Hz,1 H, aromatic), 7.38 (t, J=10 Hz, 1 H, aromatic), 7.42 (d, J=6 Hz, 1 H, aromatic), 7.49 (dd, J=8 Hz and 5 Hz, 1H, aromatic); m/z 716 (M++Na); IR (CH2 Cl2, cm-1) 1733, 1672, 1661, 1585.
PAC 17-Amino-22-(4'-methoxyphenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetale was dissolved in 1 mL chloroform and precipitated with hexanes to yield a salmon-colored solid; Yield 0.205 g (64%): mp 175-178°C; 1 H-NMR (300 MHz, CDCl3)δ0.65 (d, J=9 Hz, 3H, 14-CH3), 0.76 (m, 1H, H-13), 0.98 (d, J=8 Hz, 3H, 10-CH3), 1.32 (s, 3H, 8-CH3), 1.43 (m, 1H, H-13), 1.82 (dd, J=15 Hz and 5 Hz, 1H, H-15), 1.92 (s, 3H, 2-CH3), 2.10-2.28 (br m, 2H, H-10 and H-14), 2.40 (s,1 H,11 --OH), 2.81-2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.57 (d, J=13 Hz, 1 H, H-11), 3.83 (s, 3H, --OCH3), 4.21 (t, J=11 Hz, 1 H, H-6), 4.36 (d, J=17 Hz, 1 H, α-CH2), 4.67 (br s3, 2H, NH2), 4.98 (d, J=10 Hz, 1H, H-7), 5.11 (br s, 2H, NH2), 5.13 (d, J=12 Hz, 1H, H-9), 5.21 (t, J=12 Hz 1H, H-5), 5.89 (s, 1H, H-19), 5.94 (d, J=18 Hz, 1H, α-CH2), 6.33 (t, J=13 Hz, 1H, H-4), 6.91 (m, 2H, aromatic), 7.08 (d, J=13 Hz, 1H, H-3), 7.89 (m, 2H, aromatic); m/z 691 (M+) and 713 (M++Na); IR (CH2 Cl2, cm-1) 1732, 1673, 1661, 1586, 1507.
PAC 17-Amino-22-(2'-chlorophenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was purified by preparative centrifugally accelerated radial thin-layer chromatograpohy (ChromatotronR) using a gradient of 2-4% methanol in chloroform to give fractions containing pure product which were evaporated in vacuo to afford a red solid; Yield 0.138 g (43%): 1 H-NMR (300 MHz, CDCl3)δ0.72 (d, J=7 Hz, 3H, 14-CH3), 0.83 (m, 1H, H-13), 1.03 (d, J=6 Hz, 3H, 1-CH3), 1.40 (s, 3H, 8-CH3), 1.49 (br m,1 H, H-13), 1.91 (dd, J=13 Hz and 6 Hz, 1H, H-15), 1.99 (s, 3H, 2-CH3), 2.18-2.31 (br m, 2H, H-10 and H-14), 2.43 (s, 1 H, 11-OH), 2.38-2.46 (m, 2H, H-12 and H-15), 3.25 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.63 (d, J=8 Hz, 1H, H-11), 4.22 (t, J=10 Hz, 1H, H-6), 4.49 (d, J=19 Hz, 1H, α-CH2), 4.62 (br s, 2H, NH2), 5.02 (d, J=9 Hz, 1 H, H-7), 5.19 (s, 2H, NH2), 5.21 (d, J=12 Hz, 1 H, H-9), 5.30 (t, J=11 Hz, 1 H, H-5), 5.40 (br s, 2H, NH2), 5.83 (d, J=18 Hz, 1H, α-CH2), 6.15 (s, 1H, H-19), 6.39 (t, J=12 Hz, 1H, H-4), 6.96 (d, J=12 Hz, 1H, H-3), 7.38-7.43 (m, 1 H, aromatic), 7.48 (m, 2H, aromatic), 7.67 (m, 1,1, aromatic); m/z 720 (M+ +Na); IR (KBr, cm-1) 1722, 1680, 1661, 1590; Analysis calculated for. C3,H44 ClN3 O9 : C, 61.93; H, 6.35; N, 6.02%. Found C, 60.59; H, 6.18; N, 5.54%.
PAC 17-Amino-22-(4'-chlorophenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was dissolved in 2 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 0.087 g (27%): mp 175-178°C; 1 H-NMR (300 MHz, CDCl3)δ0.66 (d, J=7 Hz, 3H, 14-CH3), 0.76 (m, 1H, H-13), 0.98 (d, J=6 Hz, 3H, 10-CH3), 1.33 (s, 3H, 8-CH3), 1.43 (m, lH, H-13), 1.83 (dd, J=15 Hz and 4 Hz, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.10-2.27 (br m, 2H, H-10 and H-14), 2.41 (s, 1 H, 11-OH), 2.81-2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.58 (d, J=11 Hz, 1 H, H-11), 3.81 (s, 3H, OCH3), 4.21 (t, J=10 Hz, 1H, H-6), 4.36 (d, J=17 Hz, 1H, α-CH2), 4.54 (br s, 2H, NH2), 4.99 (d, J=10 Hz, 1H, H-7), 5.13 (br s, 2H, NH2), 5.15 (d, J=10 Hz, 1H, H-9), 5.22 (t, J=12 Hz 1H, H-5), 5.89 (s, 1H, H-19), 5.97 (d, J=17Hz, 1H, α-CH2), 6 34 (t, J=12Hz, 1H, H-4), 7.01 (d, J=12 Hz, 1H, H-3), 7.43 (d, J=9 Hz, 2H, aromatic), 7.87 (d, J=9 Hz, 2H, aromatic); m/z 720 (M++Na); IR (CH2 Cl2, cm-1) 1733, 1677, 1662, 1584.
PAC 17-Amino-22-phenacyl-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was purified by Chromatotron (trademark) using 2% methanol in chloroform to givfa fractions containing pure product which were evaporated in vacuo to yield a red solid. 0.161 gm (53%) mp 188-91°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.68 (d, J=5 Hz, 3H, 14-CH3), 0.80 (m, 1H, H-13), 0.98 (d, J=5 Hz, 3H, 10-CH3), 1.35 (s, 3H, 8-CH3), 1.43 (m, 1H, H-13), 1.85 (dd, J=3 Hz, J=10 Hz, 1H, H-15), 1.96 (s, 3H, 2-CH3), 2.11-2.23 (br m, 2H, H-10, H-14), 2.39 (s, 1H, 11-OH), 2.85 (m, 2H, H-12, H-15), 3.21(s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.60 (dd, J=3 Hz, J=7 Hz, 1H, H-11), 4.21 (t, J=9 Hz, 1H, H-6), 4.39 (d, J=15 Hz, 1H, α-CH), 4.61 (br s, 2H, NH2), 5.03-5.19 (m, 2H, NH2), 5.16 (d, J=8 Hz, 1H, H-9), 5.71 (t, J=8 Hz, IH, H-5), 5.89 (s, 1H, H-1 9), 6.00 (d, J=15 Hz, 1H, α-CH), 6.35 (t, J=8 Hz, 1H, H-4), 7.05 (d, J=8 Hz, 1H, H-3), 7.46 (t, J=6 Hz, 2H, aromatic), 7.60 (t, J=6 Hz, 1H, aromatic), 7.93 (d, J=6 Hz, 2H, aromatic); m/z 686 (M++Na), 664 (M++H); IR (KBr, cm-1) 1720,1670, 1655, 1580; Analysis calculated for C36 H45 N3 O9∅5H2 O: C, 64.27; H, 6.89; N, 6.27%. Found C, 64.13; H, 6.33; N, 6.19%.
PAC 17-Amino-22-(3',4'-dichlorophenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was further purified by preparative HPLC using a Zorbax column eluted with 593:1:40 ethyl acetate: methanol:hexanes. The fractions containing pure material were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipilated with hexanes to give a dark rose-colored solid; Yield 0.134 g (40%): mp 176-178°C; 1 H-NMR (300 MHz, CDCl3)δ0.63 (d, J=7 Hz, 3H, 14-CH3), 0.74 (m, 1H, H-13), 0.98 (d, J=8 Hz, 3H, 10-CH3), 1.31 (s, 3H, 8-CH3), 1.42 (m, 1H, H-13), 1.82 (dd, J=15 Hz and 5 Hz, 1H, H-15), 1.92 (s, 3H, 2-CH3), 2.09-2.24 (br m, 2H, H-10 and H-14), 2.42 (s, 1H, 11-OH), 2.78-2.88 (m, 2H, H-12 and H-15), 3.21 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.57 (d, J=10 Hz, 1H, H-11), 4.18 (t, J=11 Hz, 1H, H-6), 4.36 (d, J=19Hz, 1H, α-CH2), 4.69 (br s, 2H, NH2), 4.98 (d, J=11 Hz, 1H, H-7), 5.12 (d, J=11 Hz, 1H, H-9), 5.16 (br s, 2H, NH2), 5.21 (t, J=11 Hz, 1H, H-5), 5.85 (s, 1H, H-19), 5.92 (d, J=18 Hz, 1H, α-CH2), 6.34 (t, J=12 Hz, 1H, H-4), 6.98 (d, J=12 Hz, 1H, H-3), 7.57 (d, J=9 Hz, 1H, aromatic), 7.76 (dd, J=9 Hz and 4 Hz, 1H, aromatic), 8.01 (d, J=4 Hz, 1H, aromatic); m/z 732 (M+); IR (CH2 Cl2, cm-1) 1731, 1704, 1673, 1661, 1583.
PAC 17-Amino-22-(4'-aminophenacyl)-17-demethoxygeldanamycinFrom 4-aminophenacyl chloride: the product was a pink solid. Yield 0.066 g (21%): mp 188°C (dec); 1 H-NMR (300 MHz, CDCl3) 60.71 (d, J=8 Hz, 3H, 14-CH3), 0.86 (br m, 1 H, H-13), 1.04 (d, J=8 Hz, 3H, 10-CH3)δ1.39 (s, 3H, 8-CH3), 1.49 (br m, 1H, H-13), 1.90 (dd, J=13 Hz, 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.22 (br m, 2H, H-10, H-14), 2.48 (br s,1H, --OH), 2.92 (m, 2H, H-12 and H-15), 3.293 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.62 (d, J=10 Hz, 1H, H-11), 4.28 (s, 2H, NH2), 4.29 (t, J=9 Hz, 1H, H-6), 4.37 (d, J=18 Hz, 1H, α-CH2), 4.75 (br s, 2H, NH2), 5.03 (d, J=9 Hz, 1 H, H-7), 5.18 (br s, 2H, NH2), 5.21 (d, J=9 Hz, 1H, H-9), 5.26 (t, J=13 Hz, 1H, H-5), 5.95 (d, J=18 Hz, 1H, α-CH2), 5.96 (s, 1H, H-19), 6.49 (t, J=10 Hz, 1H, H-4), 6.66 (d, J=9 Hz, 2H, aromatic), 7.18 (d, J=13 Hz, 1H, H-3), 7.78 (d, J=9 Hz, 2H, aromatic); m/z 701 (M+ +Na); IR (KBr, cm-1) 1718, 1708, 1655, 1619, 1580.
PAC 17-Amino-22-(4'-cyanophenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetal:e was further purified by preparative HPLC using a Zorbax column eluted with a mixture comprising 59:1:40 ethyl acetate:methanol:hexanes. Fractions containing pure mate(rial were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; yield 0.0296 g (8.4%): mp 186°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.71 (d, J=6 Hz, 3H, 14-CH3), 0.83 (br m, 1H, H-13), 1.04 (d, J=6 Hz, 3H, 10-CH3),1.39 (s, 3H, 8-CH3),1.48 (m, 1H, H-13),1.90 (dd, J=11 Hz and 5 Hz,1H, H-15), 1.99 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.41 (s,1H, --OH), 2.92 (m, 2H, H-12 and H-15), 3.27 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.64 (d, J=11 Hz, 1H, H-11), 4.23 (t, J=10 Hz, 1H, H-6), 4.45 (d, J=18 Hz, 1H, α-CH2), 4.61 (br s, 2H, NH2), 5.05 (d, J=10 Hz, 1H, H-7), 5.20 (br s, 2H, NH2), 5.21 (d, J=11 Hz, 1H, H-9), 5.29 (t, J=11 Hz, 1H, H-5), 5.96 (s, 1H, H-19), 6.02 (d, J=18 Hz, 1H, α-CH2), 6.40 (t, J=11 Hz, 1H, H-4), 7.00 (d, J=11 Hz, 1H, H-3), 7.84 (d, J=8 Hz, 2H, aromatic), 8.08 (d, J=8 Hz, 2H, aromatic); m/z 712 (M+ +Na); IR (KBr, cm-1) 2220, 1721, 1701, 1672, 1655, 1580; Analysis calculated for C36 H44 N4 O11 : C, 64.52; H, 6.44; N, 8.13%. Found C, 58.56; H, 5.81; N, 7.33%.
PAC 17-Amino-22-(2'-nitrophenacyl)-17-demethoxygeldanamycinYield 0.0689 g (21%): mp 165°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.70 (d, J=7 Hz, 3H, 14-CH3), 0.82 (m, 1H, H-13), 1.03 (d, J=7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.52 (m, 1H, H-13), 1.90 (dd, J=14 Hz and 4 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.08 (s, 1H, 11-OH), 2.26 (br m, 2H, H-10 and H-14), 2.90 (m, 2H, H-12 and H-15), 3.19 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.64 (d, J=10 Hz, 1H, H-11), 4.15 (t, J=10 Hz, 1H, H-6), 4.42 (d, J=18 Hz, 1H, α-CH2), 5.01 (d, J=10 Hz, 1H, H-7), 5.10 (br s, 2H, NH2), 5.20 (d, J=9 Hz, 1H, H-9), 5.23 (br s, 2H, NH2)l, 5.26 (t, J=13 Hz, 1H, H-5), 5.63 (d, J=18 Hz, 1H, α-CH2), 6.38 (t, J=12 Hz, 1H, H-7), 6.52 (s, 1H, H-19), 6.87 (d, J=12 Hz, 1H, H-3), 7.63 (m, 1H, aromatic), 7.69 (m, 1H, aromatic), 7.80 (m, 1H, aromatic), 8.20 (m, 1H, aromatic); m/z 731 (M+ +Na); IR (KBr, cm-1) 1718, 1671, 1657, 1580, 1521; Analysis calculated for (C36 H44 N4 O11): C, 61.00; H, 6.26; N, 7.91%. Found C, 59.92; H, 6.10; N, 7.71%.
PAC 17-Amino-22-(3'-nitrophenacyl)-17-demethoxygeldanamycinYield 0.0225 g (6.9%); 1 H-NMR (300 MHz, CDCl3)δ0.71 (d, J=8 Hz, 3H, 14-CH3), 0.88 (m, 1H, H-13), 1.04 (d, J=8 Hz, 3H, 10-CH3), 1.34 (s, 3H, 8-CH3), 1.42 (m, 1H, H-13), 1.90 (dd, J=13 Hz and 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.42 (br s, 1H, --OH), 2.93 (m, 2H, H-12 and H-15), 3.29 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.64 (d, J=10 Hz, 1H, H-11), 4.23 (t, J=9 Hz, 1H, H-6), 4.52 (d, J=18 Hz, 1H, α-CH2), 4.62 (br s, 2H, NH2), 5.06 (d, J=9 Hz, 1H, H-7), 5.15 (br s, 2H, NH2), 5.21 (d, J=9 Hz, 1H, H-9), 5.30 (t, J=13 Hz, 1H, H-5), 5.98 (s, 1H, H-19), 6.06 (d, J=18 Hz, 1H, α-CH2), 6.41 (t, J=9 Hz, 1H, H-4), 7.00 (d, J=13 Hz, 1H, H-3), 7.76 (t, J=8 Hz, 1H, aromatic), 8.32 (d, J=8 Hz, 1H, aromatic), 8.52 (d, J=8 Hz, 1H, aromatic), 8.83 (s, 1H, aromatic); m/z 731 (M+ +Na); IR (KBr, cm-1) 1719, 1664, 1652, 1580, 1521.
PAC 17-Amino-22-(4'-nitrophenacyl)-17-demethoxygeldanamycinThe residue obtained upon evaporation of the ethyl acetate was further purified by preparative HPLC using a Zorbax column eluted with 59:1:40 ethyl acetate:methanol: hexanes. Fractions containing pure material were evaporated in vacuo then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark rose-colored solid; Yield 0.0175 g (1.3%): mp; 1 H-NMR (300 MHz, CDCl3)δ0.70 (d, J=7 Hz, 3H, 14-CH3), 0.82 (m, 1H, H-13), 1.02 (d, J=7 Hz, 3H, 10-CH3), 1.38 (s, 3H, 8-CH3), 1.50 (m, 1 H, H-13), 1.90 (dd, J=16 Hz and 4 Hz, 1 H, H-15), 2.00 (s, 3H, 2-CH3), 2.25 (br m, 2H, H-10 and H-14), 2.50 (br s, 1H, 11-OH), 2.89 (m, 2H, H-12 and H-15), 3.27 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.63 (d, J=10 Hz, 1H, H-11), 4.23 (t, J=10 Hz, 1H, H-6), 4.50 (d, J=18 Hz, 1H, α-CH2), 4.77 (s, 2H, NH2), 5.03 (d, J=10 Hz, 1H, H-7), 5.20 (d, J=11 Hz, 1H, H-9), 5.25 (br s, 2H, NH2), 5.28 (t, J=11 Hz, 1H, H-5), 5.96 (s, 1H, H-19), 6.03 (d, J=18 Hz, 1H, α-CH2), 6.40 (t, J=12 Hz, 1H, H-4), 6.99 (d, J=12 Hz, 1H, H-3), 8.15 (d, J=9 Hz, 2H, aromatic), 8.37 (d, J=9 Hz, 1H, aromatic); m/z 731 (M+ +Na); IR (KBr, cm-1) 1660, 1590.
PAC 17-Amino-22-(4'-azidophenacyl)-17-demethoxygeldanamycin17-Amino-17-demethoxygeldanamycin (0.500 g, 0.92 mmol) was dissolved in 25 mL of acetone (stored over potassium carbonate) and 1.27 g potassium carbonate was added (9.17 mmol, 10 eq). The reaction was stirred in the dark for 24 hours, filtered, concentrated in vacuo to a residue which was flash chromatographed through silica gel using 69:1:30 ethyl acetate:methanol:hexanes. The product was dissolved in 1 mL chloroform and precipitated with hexanes to give a rose-colored solid; Yield 0.095 g (15%): mp 165-167°C; 1 H-NMR (300 MHz, CDCl3)δ0.65 (d, J=8 Hz, 3H, 14-CH3), 0.76 (m, 1H, H-13), 0.97 (d, J=8 Hz, 3H, 10-CH3), 1.32 (s, 3H, 8-CH3), 1.42 (m, 1H, H-13), 1.82 (dd, J=15 Hz and 5 Hz, 1H, H-15), 1.91 (s, 3H, 2-CH3), 2.09-2.27 (br m, 2H, H-10 and H-14), 2.41 (br s, 1H, 11-OH), 2.79-2.90 (m, 2H, H-12 and H-15), 3.21 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.58 (d, J=11 Hz, 1H, H-11), 4.20 (t, J=10 Hz, 1H, H-6), 4.36 (d, J=17 Hz, 1H, α-CH2), 4.65 (br s, 2H, NH2), 4.98 (d, J=10 Hz,1H, H-7), 5.11 (br s, 2H, NH2), 5.14 (d, J=10 Hz, 1H, H-9), 5.20 (t, J=12 Hz, 1H, H-5), 5.89 (s, 1H, H-19), 5.95 (d, J=17 Hz, 1H, α-CH), 6.33 (t, J=13 Hz, 1H, H-4), 7.02 (d, J=13 Hz, 1H, H-3), 7.08 (d, J=9 Hz, 2H, aromatic), 7.91 (d, J=9 Hz, 2H, aromatic); m/z 705 (M+ +H); Analysis calculated for C36 H44 N6 O9∅2H2 O: C, 58.37; H, 6.53; N, 11.34%; Found C, 58.37:, H, 5.85;N, 11.08%.
PAC 17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycinPotassium chloride (0.022 g, 0.29 mmol) was dissolved in 1 mL water and poured into iodine monochloride (0.043 g, 0.27 mmol). This mixture was poured into a solution of the title compound of Example 41 (0.139 g, 0.2 mmol) in 24 mL 0.1N hydrochloric acid and 3 mL methanol. After stirring for 2 hours at room temperature the reaction was quenched with sodium bisulfite. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 3N hydrochloric acid, saturated sodium bicarbonate, water and brine, dried over magnesium sullate and filtered. The residue obtained upon removal of the solvent was dissolved in 1 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 0.099 g (60%): 1 H-NMR (300 MHz, CDCl3)δ0.66 (d, J=7 Hz, 3H, -CH3), 0.75 (m, 1H, H-13), 0.98 (d, J=6 Hz, 3H, 10-CH3), 1.34 (s, 3H, 8-CH3), 1.47 (m, 1H, H-13), 1.91 (m, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.10-2.29 (br m, 2H, H-10 and H-14), 2.59 (s,1 H, 11-OH), 2.78-2.92 (m, 2H, H-12 and H-15), 3.25 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.59 (d, J=10 Hz, 1H, H-11), 4.24 (t, J=10 Hz, 1H, H-6), 4.32 (d, J=18 Hz, 1H, α-CH2), 4.56 (s, 2H, NH2), 4.95 (d, J=10 Hz, 1H, H-7), 5.04 (br s, 2H, NH2), 5.15 (d, J=11 Hz, 1H, H-9), 5.22 (t, J=11 Hz, 1 H, H-5), 5.58 (br s, 2H, NH2), 5.88 (d, J=18 Hz, 1 H, α-CH2), 5.89 (s, 1H, H-19), 6.37 (t, J=12 Hz, 1H, H-4), 6.60 (dd, J=9 Hz and 3 Hz, 1H, aromatic), 7.06 (d, J=12 Hz, 1H, H-3), 7.71 (dd, J=9 Hz and 2 Hz, 1H, aromatic), 8.22 (dd, J=2 Hz and 3 Hz, 1H, aromatic) IR (KBr, cm-1) 1715, 1660, 1610, 1580.
The acid washes were neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate, filtered and stripped to recover the title compound of Example 41, Yield 0.045 g (27%).
PAC 17-Amino-22-(4'-azido-3'-iodophenacyl)-17-demethoxygeldanamycin17-Amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycin, from Example 47, (0.036 g, 0.44 mmol) was dissolved in 89 mL methanol, cooled to 0°C and shielded from light. To this solution was added 45 mL 1N hydrochloric acid and 45 mL 0.5N sodium nitrite. After 15 minutes of stirring, an additional 45 ml 0.5N sodium azide was added and the reaction mixture stirred another 15 minutes at 0°C The resulting solution was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate, filtered and stripped to give a red glass which was dissolved in 1 mL ethyl acetate and precipitated with hexanes. Yield 0.027 g (72%): 1 H-NMR (300 MHz, CDCl3)δ0.69 (d, J=7 Hz, 3H, 14-CH3), 0.79 (m, 1 H, H-13), 1.03 (d, J=8 Hz, 3H, 10-CH3), 1.50 (s, 3H, 8-CH3), 1.89 (m, 2H, H-13 and H-15), 1.99 (s, 3H, 2-CH3), 2.11-2.32 (br m, 2H, H-10 and H-14), 2.53 (br s, 1 H, 11-OH), 2.81 -2.95 (m, 2H, H-12 and H-15), 3.28 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.62 (d, J=9 Hz, 1H, H-11), 4.22 (t, J=12 Hz, 1H, H-6), 4.41 (d, J=17 Hz, 1H, α-CH2), 4.80 (br s, 2H, NH2), 5.02 (d, J=9 Hz, 1H, H-7), 5.16-5.31 (br m, 4H, NH2, H-9, and H-5), 5.92 (s, 1H, H-19), 5.99 (d, J=18 Hz, 1H, α-CH2), 6.40 (t, J=14 Hz, 1H, H-4), 7.03 (d, J=14 Hz, 1H, H-3), 7.12 (m, 1H, aromatic), 8.00 (m, 2H, aromatic), 8.40 (m, 1H, aromatic); IR (KBr, cm-1) 1722, 1680, 1661, 1580.
The compounds of Examples 49 and 50 were prepared according to the method of Example 32.
PAC 17-Amino-22-(4'-phenylphenacyl)-17-demethoxygeldanamycinYield 0.119g (35%): mp 193-195°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.72 (d, J=7 Hz, 3H, 14-CH3), 0.83 (m, 1 H, H-13), 1.04 (d, J=7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.49 (m, 1H, H-13), 1.90 (dd, J=16 Hz and 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-H3), 2.25 (br m, 2H, H-10 and H-14), 2.47 (s,1 H, 11-OH), 2.91 (m, 2H, H-12 and H-15), 3.31 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.64 (d, J=10 Hz, 1H, H-11), 4.29 (t, J=10 Hz, 1H, H-6), 4.49 (d, J=18 Hz, 1H, α-CH2), 4.72 (br s, 2H, NH2), 5.04 (d, J=10 Hz, 1H, H-7), 5.17 (br s, 2H, NH2), 5.21 (d, J=11 Hz, 1H, H-9), 5.28 (t, J=11 Hz, 1H, H-5), 5.99 (s, 1H, H-19), 6.09 (d, J=18 Hz, 1H, α-CH2), 6.41 (t, J=12 Hz, 1H, H-4), 7.13 (d, J=12 Hz, 1H, H-3), 7.47 (m, 3H, aromatic), 7.12 (m, 3H, aromatic), 7.74 (d, J=8 Hz, 2H, aromatic), 8.05 (d, J=8 Hz, 2H, aromatic); m/z 731 (M+ +Na+).
PAC 17-Amino-22-(2-acetonaphthyl)-17-demethoxygeldanamycinThe crude title compound, prepared from 2-(2'-bromoacetyl)naphthalene was dissolved in 1 mL chloroform and precipitated with hexanes to give a salmon-colored solid; Yield 0.163 g (50%): mp 185-187°C; 1 H-NMR (300 MHz, (CDCl3)δ0.71 (d, J=8 Hz, 3H, 14-CH3), 0.82 (m, 1H, H-13), 1.02 (d, J=7 Hz, 3H, 10-CH3), 1.40 (s, 3H, 8-CH3), 1.49 (m, 1H, H-13), 1.89 (dd, J=15 Hz and 5 Hz, 1H, H-15), 2.00 (s, 3H, 2-CH3), 2.22 (br m, 2H, H-10 and H-14), 2.44 (s,1H, 11-OH), 2.91 (m, 2H, H-12 and H-15), 3.30 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.51 (d, J=11 Hz, 1H, H-11), 4.30 (t, J=11 Hz, 1H, H-6), 4.59 (d, J=19 Hz, 1H, α-CH2), 4.68 (br s, 2H, NH2), 5.02 (d, J=10 Hz, 1H, H-7), 5.15 (br s, 2H, NH2), 5.20 (d, J=13 Hz, 1H, H-9), 5.28 (t, J=13 Hz, 1H, H-5), 6.00 (s, 1H, H-19), 6.20 (d, J=17 Hz, 1H, α-CH2), 6.40 (t, J=12 Hz, 1H, H-4), 7.13 (d, J=13 Hz,1H, H-3), 7.54-7.68 (m, 2H, aromatic), 7.87-8.02 (m, 2H, aromatic), 8.51 (s, 1H, aromatic); m/z 714 (M+) and 736 (M ++Na); IR (CH2 Cl2, cm-1) 1733,1677, 1662, 1585.
PAC 17-Azetidin-1-yl-11-α-fluoro-17-demethoxygeldanamycin17-Azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.342 mmol) was added to a flame dried flask under nitrogen and dissolved in 15 mL of methylene chloride. The mixture was cooled to -68°C with an external dry ice/acetone bath and then a solution of DAST (0.055g, 0.342 mmol, 0.045 mL) in 2.5 mL of methylene chloride was added dropwise. After 1 hour 5 mL of 5% aqueous NaHCO3 was addded slowly and the product extracted into 100 mL of methylene chloride. The organic layer was washed with 3×50 mL of water and 2×50 mL of brine, dried with MgSO4, filtered and stripped of solvent to afford a purple solid. This was purified by flash column chromatography using 5% methanol in chloroform. Material of Rf═0.42 (1:9 methanol: chloroform), the desired product, (0.058 g 29%) was disolved in a minimal amount of ethyl acetate and precipitated with hexanes; Yield 0.042 g (21%), mp 128°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.05(m, 6H: 10-CH3 and 14-CH3), 1.25 (br t, J=15 Hz, 1H, H-13), 1.55 (br t, J=15 Hz, 1H, H-13), 1.78 (s, 3H, 8-CH3), 1.96 (br m, 1H, H-14), 2.03 (s, 3H, 2-CH3), 2.23 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.40 (br m, 2H, 3' azetidine CH2), 2.55 (dd, J=7 Hz, 16 Hz, 1H, H-15), 2.80 (br d, J=26 Hz, 1H, H-10), 3.35 (s, 3H, OCH3), 3.37 (s, 3H, OCH3), 3.53 (br m, 1H, H-12), 4.39 (d, J=9 Hz, 1H, H-6), 4.0 (br m, 7H, NH2 and 2' and 4' azetidine CH2 and H-11), 5.60 (d, J=9Hz, 1H, H-9), 5.70(s, 1H, H-7), 5.88 (t, J=9 Hz, 1H, H-5), 6.55 (t, J=9Hz, 1H, H-4), 6.96 (d, J=9 Hz, 1H, H-3), 7.05 (s, 1H, H-19), 9.33 (s, 1H, NH-22); m/z 610. (M++Na); IR (KBr, cm-1) 1735,1690, 1650; Analysis calculated for C31 H42 FN3 O7.5H2 O: C, 54.93; H, 7.73; N, 6.20%. Found: C, 55.07; H, 6.23; N, 6.07%.
The compounds of Examples 52-58 were prepared by ttle method of Example 51 from the appropriately substituted 17-amino-17-demethoxygelcdanamycin derivatives.
PAC 17-Amino-11-α-fluoro-17-demethoxygeldanamycinYield 0.155 g (44%), mp >250°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.80 (d, 3H, J=8Hz, 10-CH3), 0.90 (d, 3H, J=8Hz, 14-CH3), 0.93 (br m, 1H, H-13), 1.35 (br t, 1H, H-13), 1.60 (s, 3H, 8-CH3), 1.85 (s, 3H, 2-CH3), 1.85 (br m, 1H, H-14), 1.85-2.1 (br m, 2H, H-15), 2.63 (br d, J=26 Hz, 1H, H-10), 3.16 (s, 6H, OCH3), 3.26 (br m, 1H, H-12), 4.28 (d, J=9Hz, 1H, H-6), 4.45 (br d, J=47 Hz, 1H, H-11), 4.60 (br m, 2H, NH2), 4.95 (s, 1H, H-7), 5.07 (br s, 2H, NH2), 5.45 (d, J=9 Hz, 1H, FH-9), 5.70 (t, J=9 Hz, 1H, H-5), 6.35 (t, J=9 Hz, 1H, H-4), 6.80 (d, J=9 Hz, 1H, H-3), 7.05 (s, 1H, H-19), 9.0 (s, 1H, NH-22); m/z 570. (M++Na); IR (KBr, cm-1) 1715, 1685, 1670; Analysis calculated for C28 H38 FN3 O7∅25H2 O: C, 60.91; H, 7.03; N, 7.61%. Found: C, 60.78; H, 6.87; N, 7.43%.
PAC 17-Isopropylamino-11-α-fluoro-17-demethoxygeldanamycinYield 0.035 g (16%), mp 132°C; 1 H-NMR (300 MHz, CDCl3)δ0.85 (m, 6H, 10-CH3, 14-CH3), 0.85 (m, 1H, H-13), 1.07 and 1.11 (br d, J=8 Hz, 6H, isopropyl CH3), 1.38 (br m, 1H, H-13), 1.60 (s, 3H, 8-CH3), 1.71 (br m, 1H, H-14), 1.75 (s, 3H, 2-CH3), 2.15 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.45 (dd, J=7 Hz, 16 Hz, 1H, H-15), 2.65 (br d, J=26 Hz, 1H, H-10), 3.19 and 3.20 (br s, 6H, OCH3), 3.35 br m, 1H, H-1 2), 3.95 (m, 1H, isopropyl CH), 4.22 (d, J=9 Hz, 1H, H-6), 4.30 (br d, J=47 Hz, 1H, H-11), 4.65 (br m, 2H, NH2), 5.04 (s, 1H, H-7), 5.46 (d, J=9 Hz, 1H, H.9), 5.73 (t, J=9 Hz, 1H, H-5), 5.94 (br d, J=10.5 Hz, 1H, NH), 6.40 (t, J=9Hz, 1 H-4), 6.80 (d, J=9 Hz, 1H, H-3), 7.05 (s, 1H, H-19), 9.15 (s, 1H, NH-22); m/z 612. (M++Na); IR (KBr, cm-1) 1740, 1705, 1655; Analysis calculated for C31 H44 FN3 O7∅5H2 O: C, 62.19; H,7.57; N, 7.01%. Found: C, 62.36; H, 7.48; N, 6.81%.
PAC 17-Cyclopropylamino-11-α-fluoro-17-demethoxygeldanamycinYield 0.056 g (25%), mp 119°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.70 (m, 2H, cyclopropyl CH2), 0.86 (m, 3H, cyclopropyl CH2 and H-13), 0.92 (d, 3H, J=8Hz, 10-CH3), 1.00 (d, 3H, J=8Hz, 14-CH3), 1.53 (br m, 1H, H-13), 1.70 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 2.00 (br m, 1H, H-14), 2.62 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.70 (br d, J=26 Hz, 1H, H-10), 2.80 (m, 1H, cyclopropyl CH), 2.90 (dd, J=7 Hz, 16 Hz, 1H, H-15), 3.33 (s, 6H, OCH3), 3.45 (br m, 1H, H-12), 4.33 (d, J=9 Hz, 1H, H-6), 4.36 (br d, J=47 Hz, 1H, H-11), 4.7 (br m, 2H, NH2), 5.10 (s, 1H, H-7), 5.55 (d, J=9 Hz, 1H, H-9), 5.75 (t, J=9 Hz, 1H, H-5), 6.20 (br t, 1H, NH), 6.46 (t, J=9 Hz, 1H, H-4), 6.90 (d, J=9 Hz, 1H, H-3), 7.15 (s, 1H, H-19), 9.15 (s, 1H, NH-22); m/z 610. (M++Na); IR (KBr, cm-1) 1740, 1690, 1630; Analysis calculated for C31 H42 FN3 O7.1.5H2 O: C, 60.57; H, 7.37; N, 6.83%. Found: C, 60.43; H, 6.79; N, 6.83%.
PAC 17-Allylamino-11-α-fluoro-17-demethoxygeldanamycinYield 0.049 g (25%), mp 110-112°C; 1 H-NMR (300 MHz, CDCl3)δ0.85(d, 3H, J=8Hz, 10-CH3), 0.88(d, 3H, J=8Hz, 14-CH3), 1.45 (br m, 2H, H-13), 1.63 (s, 3H, 8-CH3), 1.86 (s, 3H, 2-CH3), 1.88 (br m, 1H, H-14), 2.20 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.55 (dd, J=7 Hz, 16 Hz, 1H, H-15), 2.80 (br d, J=26 Hz, 1H, H-10), 3.20 (s, 6H, OCH3), 3.33 (br m, 1H, H-12), 3.95 (br t, 2H, allylic CH2), 4.23 (d, J=9 Hz, 1 H, H-6), 4.26 (br d, J=49 Hz, 1H, H-11), 4.57 (br m, 2H, NH2), 5.03 (s, 1 H, H-7), 5.15 (br d, 2H, vinylic CH2), 5.45 (d, J=9 Hz, 1H, H-9), 5.55 (m, 2H, H-5 and vinylic CH), 6.10 (br t, 1H, NH), 6.40 (t, J=9 Hz, 1H, H-4), 6.80 (d, J=9 Hz, 1H, H-3), 7.07 (s, 1H, H-19), 9.13 (s, 1H, NH-22); m/z 608. (M++Na); IR (KBr, cm-1) 1740, 1700, 1655; Analysis calculated for C31 H42 FN3 O7∅75H2 O: C, 61.93; H, 7.24; N, 6.98%. Found: C, 61.87; H, 6.93; N, 7.00%.
PAC 17-Propargylamino-11-α-fluoro-17-demethoxygeldanamycinYield 0.051 g (27%), mp 111°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.83 (br m, 1H, H-13), 0.95 (d, 3H, J=8Hz, 10-CH3), 0.98 (d, 3H, J=8Hz, 14-CH3), 1.53 (br m, 1H, H-13), 1.73 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 1.94 (br m, 1H, H-14), 2.35 (s, 1H, acetylene CH), 2.35 (dd, J=8.5 Hz, 16 Hz, 1 H, H-15), 2.58 (dd, J=7 Hz, 16 Hz, 1 H, H-15), 2.65 (br d, J=26 Hz, 1H, H-10), 3.3 (s, 6H, OCH3), 3.45 br m, 1H, H-12), 4.20 (br s 2H, propargyl CH2), 4.33 (d, J=9 Hz, 1H, H-6), 4.36 (br d, J=47 Hz, 1H, H-11), 4.8 (br m, 2H, NH2), 5.13 (s, 1H, H-7), 5.57 (d, J=9 Hz, 1H, H-9), 5.85 (t, J=9 Hz, 1H, H-5), 6.13 (br t, 1H, NH), 6.50 (t, J=9 Hz, lH, H-4), 6.90 (d, J=9 Hz, 1H, H-3), 7.20 (s, 1H, H-19), 9.13 (s, 1H, NH-22); m/z 608. (M++Na); IR (KBr, cm-1) 2120, 1735, 1695,1635; Analysis calculated for C3, H40 FN3 O7∅75H2 O: C, 62.14; H, 6.98; N, 7.01%. Found: C, 61.99; H, 6.71; N, 6.90%.
PAC 17-(2'-Cyanoethylamino)-11-α-fluoro-17-demethoxygeldanamycinYield 0.026 g (14%), mp 122-24°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.15 (br m, 1H, H-13), 1.12 (d, 3H, J=8Hz, 10-CH3), 1.17 (d, 3H, J=8Hz, 14-CH3), 1.65 (br t, 1H, H-13), 1.75 (s, 3H, 8-CH3), 1.90 (s, 3H, 2-CH3), 2.1 (br m, 1H, H-14), 2.40 (dd, J=8.5 Hz, 16Hz, 1H, H-15), 2.65 (dd, J=7Hz, 16 Hz, 1H, H-15), 2.83 (t, J=8Hz, 2H, β-ethyl CH2), 2.93 (br d, J=26 Hz, 1H, H-10), 3.46 (s, 6H, OCH3), 3.45 (br m, 1H, H-12), 3.56 (q, J=8Hz, 2H, α-ethyl CH2), 4.46 (d, J=9 Hz, 1H, H-6), 4.55 (br d, J=47 Hz, 1H, H-11), 4.85 (br m, 2H, NH2), 5.26 (s, 1H, H-7), 5.73 (d, J=9 Hz, 1H, H-9), 6.00 (t, J=9 Hz, 1H, H-5), 6.07 (br t, 1H, NH), 6.65 (t, J=9 Hz, 1H, H-4), 7.07 (d, J=9 Hz, 1H, H-3), 7.35 (s, 1H, H-19), 9.25 (s, 1H, NH-22); m/z 623. (M++Na); IR (KBr, cm-1) 2350, 1730, 1695, 1630; Analysis calculated for C31 H41 FN4 O7 : C, 61.99; H, 6.88; N, 9.33%. Found: C, 61.52; H, 6.91; N, 9.25%.
PAC 17-(2'-Fluoroethylamino)-11-α-fluoro-17-demethoxygeldanamycinYield 0.064 g (32%), mp 134°C (dec); 1 H-NMR (300 MHz CDCl3)δ1.05 (br m, 1H, H-13), 1.03 (d, 3H, J=8Hz, 10-CH3), 1.07 (d, 3H, J=8 Hz, 14-CH3), 1.57 (br t, 1H, H-13), 1.77 (s, 3H, 8-CH3), 2.0 (br m, 1H, H-14), 2.05 (s, 3H, 2-CH3), 2.35 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.63 (dd, J=7 Hz, 16 Hz, 1H, H-15), 2.83 (br d, J=26 Hz, 1H, H-10), 3.4 (s, 6H, OCH3), 3.53 (br m, 1H, H-12), 3.85 (two br d m, J=27 Hz, 2H, α-ethyl CH2), 4.4 (d, J=9Hz, 1H, H-6), 4.45 (br d, J=47Hz, 1H, H-11), 4.65 (two br d t, J=46 Hz 7 Hz, 2H, β-ethyl CH2), 4.75 (br m, 2H, NH2), 5.23 (s, 1H, H-7), 5.63 (d, J=9 Hz, 1H, H-9), 5.90 (t, J=9 Hz, 1H, H-5), 6.25 (br t, 1H, NH), 6.57 (t, J=9 Hz, 1H, H-4), 6.97 (d, J=9 Hz, 1H, H-3), 7.25 (s, 1H, H-19), 9.25 (s, 1H, NH-22); m/z 596. (M++Na); IR (KBr, cm-1) 1740, 1700, 1630; Analysis calculated for C30 H41 F2 N3 O7 : C, 60.69; H, 6.96; N, 7.07%. Found: C, 60.23; H, 6.99; N, 7.02%.
PAC 11-α-Fluoro-geldanamycinThe title compound was prepared from geldanamycin by the method of Example 51; Yield 0.064 g (32%), mp 232°C (dec); 1 H-NMR (300 MHz, (CD3)δ0.87 (d, 3H, J=8Hz, 10-CH3), 1.00 (d, 3H, J=8Hz, 14-CH3), 1.0 (br m, 1H, H-13), 1.4 (br t, 1H, H-13), 1.73 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 1.9 (br m, 1H, H-14), 2.25 (dd, 1H, J=7 Hz, 16 Hz, 1H, H-15), 2.45 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.75 (br d, J=26 Hz, 1H, H-10), 3.3 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.4 (br m, 1H, H-12), 4.05 (s, 3H, 17-OCH3), 4.27 (d, J=9 Hz, 1H, H-6), 4.57 (br d, J=47 Hz, 1H, H-11), 4.7 (br m, 2H, NH2), 5.05 (s, 1H, H-7), 5.53 (d, J=9 Hz, 1H, H-9), 5.85 (t, J=9 Hz, 1H, H-5), 6.50 (t, J=9 Hz, 1H, H-4), 6.85 (d, J=9 Hz, 1H, H-3), 7.20 (s, 1H, H-19), 8.65 (s, 1H, NH-22); m/z 585. (M++Na); IR (KBr, cm-1) 1740, 1705, 1655; Analysis calculated for C29 H39 FN2 O8∅25H2 O: C, 61.41; H, 7.02; N, 4.93%. Found: C, 61.03; H, 6.65; N, 4.92%.
PAC 17-(S)-2'-Hydroxypropylamino-11-α-fluoro-17-demethoxygeldanamycinThe title compound of Example 59 (0.307 g, 0.546 mmol, was slurried in 6 mL of chloroform and treated with (S)-2-hydroxypropylamine (0.205 9, 2.73 mmol) at 22°C for 16 hours. The reaction mixture was diluted with 50 mL of chloroform and washed with 3×50 mL of brine and 3×50 mL of water. The organic layer was dried with MgSO4, filtered and vacuum evaporated to a purple solid. Flash column chromatography on silica gel eluted with 3% methanol in chlcroform afforded pure product; Yield 0.070 g (21%), mp 119°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.95 (br t, 7H, H-13 and 10-CH3 and γ-propyl CH3), 1.25 (d, 3H, J=8Hz, 14-CH3), 1.50 (br t, 1H, H-13), 1.70 (s, 3H, 8-CH3), 1.9 (br m, 1H, H-14), 1.97 (s, 3H, 2-CH3), 2.33 (dd, J=8.5 Hz, 16 Hz, 1H, H-15), 2.53 (dd, J=7 Hz, 16 Hz, 1H, H-15), 2.75 (br d, J=26 Hz, 1H, H-10), 3.30 (s, 6H, OCH3), 3.30 (m, 1H, α-propyl CH), 3.45 (br m, 1H, H-12), 3.57 (m, 1H, α-propyl CH), 4.0 (m,1H, γ-propyl CH), 4.33 (d, J=9 Hz, 1H, H-6), 4.37 (br d, J=27 Hz, 1H, H-11), 4.75 (br m, 2H, NH2), 5.15 (s, 1H, H-7), 5.55; (d, J=9 Hz, 1H, H-9), 5.85 (t, J=9 Hz, 1H, H-5), 6.43 (br t, 1H, NH), 6.50 (t, J=9 Hz, 1H, H-4), 6.90 (d, J=9 Hz, 1H, H-3), 7.15 (s, 1H, H-19), 9.23 (s, 1H, NH-22); m/z 628. (M++Na); IR (KBr, cm-1) 1735, 1695, 1655; Analysis calculated for C31 H44 FN3 O8∅25H2 O: C, 61.01; H, 7.35; N, 6.88%. Found: C, 60.90; H, 7.40; N, 6.74%.
PAC 17-Allyamino-11-aminocarbonyl-17-demethoxyqeldanamifcin17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Sodium isocyanate (0.311 g, 0.4.78 mmol) and trifluoroacetic acicl (0.545 g, 4.78 mmol, 0.368 mL) were added during 10 minutes. After stirring for 16 hours at room temperature, the reaction mixture was diluted with 200 mL of wal:er and extracted with 3×150 mL of chloroform. The combined organic layers were washed with 2×100 mL of water, dried with sodium sulfate, filtered and evaporated in vacuo to yield a residue, 0.236 g, which was flash chromatographed on 80 g of silica gel eluted with 69:1:30 ethyl acetate:methanol:hexanes. Fractions containing pure product were evaporated, taken up in 2 mL of chloroform and then precipitated with hexanes; 0.062 g (29%) mp 214-216°C; 1 H-NMR (300 MHz, CDCl3)δ0.93(d, J=8Hz, 3H, 10-CH3), 0.98(d, J=8Hz, 3H, 14-CH3), 1.26 (br m, 1 H, H-13), 1.50 (m, 1H, H-13), 1.69 (s, 3H, 8-CH3), 1.77 (br m, 1H, H-14), 1.96 (s, 3H, 2-CH3), 2.24 (dd, J=16 Hz and 7 Hz, 1H, H-15), 2.56 (m, 1H, H-15), 2.85 (m, 1H, H-10), 3.31 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.46 (br m, 1H, H-12), 4.05 (br t, 2H, allylic CH2), 4.39 (br m, 2H, NH2), 4.43(br d, J=9 Hz, 1H, H-6), 4.71 (v br s, 2H, NH2) 4.75 (m, 1H, H-11), 5.15-5.3 (m, 4H, vinylic CH2, H-7, H-9), 5.73-5.9 (br m, 2H, H-5, vinylic CH), 6.15 (br t, 1H, NH), 6.48 (t, J=9 Hz, 1H, H-4), 7.11 (s, 1H, H-19), 7.23 (br m, 1H, H-3), 9.20 (s, 1H, NH-22); m/z 651. (M++Na); IR (KBr, cm-1) 1740, 1725, 1705, 1680, 1645 1585, 1470; Analysis calculated for C32 H44 N4 O9.5H2 O: C,58.61; H, 7.22; N, 8.54%. Found: C, 58.50; H, 6.51; N, 8.48%.
PAC 17-Azetidin-1-yl-11-N-BOC-β-alanyl-17-demethoxygeldanimycin17-Azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341 mmol) was dissolved in 6 mL of dry methylene chloride and treated with N-BOC-β-alanine (0.077 g, 0.409 mmol), dicyclohexylcarbodiimide (0.084 g, 0.409 mmol) and dimethylaminopyridine (DMAP) (0.050 g, 0.409 mmol). After 24 hours the mixture was filtered to remove dicyclohexylurea and concentrated in vacuo to a residue which was dissolved in 200 mL of ethyl acetate and washed with 2×100 mL each of 1N hydrochloric acid, water and brine. The organic layer was dried with Na2 SO4, filtered and evaporated in vacuo to yield a purple residue (0.240 g). This was flash chromatographed on silica gel eluted with 69:1:30 ethyl acetate:methanol:hexanes. Fractions containing pure product were evaporated to yield a residue which was dissolved in 1 mL of chloroform and precipitated with 100 mL of hexane; yield 0.098 g (38%) mp 122-125°C; 1 H-NMR (300 MHz, CDCl3)δ0.87 (d, J=8 Hz, 3H, 10-CH3), 0.95 (d, J=8 Hz, 3H, 14-CH3), 1.17 (m, 1H, H-13), 1.6 (m, 1H, H-14), 1.63 (s, 3H, 8-CH3), 1.90 (m, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.35 (pent, J=8 Hz, 2H, 3'- azetidine CH2), 2.46 (m, 2H, α-alanyl CH2), 2.6-2.8 (m, 2H, H-15, H-10), 3.25 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.35 (m, 2H, β-alanyl CH2), 3.66 (m, 1H, H-12), 4.46 (d, J=8 Hz, 1H, H-6), 4.55 (t, J=8 Hz, 4H, 2' and 4' azetidine CH2), 4.44.9 (br s, 2H, NH2), 5.06 (d, J=12 Hz, 1H, H-11), 5.15 (br t, 1H, alanyl NH), 5.27 (d, J=11 Hz, 1H, H-9), 5.53 (br s, 1H, H-7), 5.80 (t, J=9, 1H, H-5), 6.45 (t, J=9 Hz, 1H, H-4), 6.90 (s, 1H, H-19), 7.00 (m, J=9 Hz, 1H, H-3), 9.40 (s, 1H, NH-22); m/z 759. (M++Na); IR (KBr, cm-1) 1732, 1645, 1583, 1541, 1477; Analysis calculated for C39 H56 N4 O11.2H2 O: C, 59.08E; H, 7.63; N, 7.07%. Found: C, 59.20; H, 7.11; N, 7.16%.
PAC 17-Ayzetidin-1-yl-11-β-alanyl-17-demethoxyaeldanamycinThe product of Example 62 (0.050 g, 0.066 mmol) was dissolved in 1 mL of trifluoroacetic acid at 0°C After 10 minutes the reaction mixture was evaporated in vacuo to a residue which was dissolved in 0.3 mL of methanol and precipitated with 20 mL of isopropylether; 0.35 g (71%) mp 138-142° C,. 1 H-NMR (300 MHz, CDCl3)δ0.84 (d, J=8 Hz, 3H, 10-CH3), 0.96 (d, J=8 Hz, 3H, 14-CH3), 1.24 (m, 1 H, H-13), 1.55 (m, 1H, H-13), 1.61 (s, 3H, 8-CH3), 1.94 (s, 3H, 2-CH3), 1.96 (m, 1H, H5), 2.35 (pent, J=8 Hz, 2H, 3' azetidine CH2), 2.6-2.8 (m, 4H, α-alanyl CH2 and H-15 and H-10), 3.18 (m, 2H, β-alanyl CH2), 3.25 (s, 6H, OCH3), 3.65 (m, 1H, H-12), 4.43 (br s, 1H, H-6), 4.57 (m, 4H, 2' and 4' azetidine CH2), 5.0-5.5 (br s, 2H, NH2), 5.15 (d, J=12 Hz, 1H, H-11), 5.3 (br m, 1H, H-9), 5.4 (br s, 1H, H-7), 5.78 (t, J=9 Hz, 1H, H-5), 6.44 (t, J=9 Hz, 1H, H-4), 6.85-7.00 (m, J=9 Hz, 1H, H-3), 6.93 (s, 1H, H-19), 8.16 (br s, 2H, alanyl NH2), 9.35 (s, 1H, NH-22); m/z 657. (M++H); IR (KBr, cm-1) 1731, 16838, 1647 1583, 1601, 1541, 1474; Analysis calculated for C34 H48 N4 O9.3H2 O: C, 52.42; H, 6.72; N, 6.79%. Found: C, 52.23; H, 6.22; N, 6.61%.
PAC 17-Azetidin-1-yl-11-[N-(4-azidobenzoyl)-β-alanyl]-17-demethoxygeldanam ycinThe title compound of Example 63 (0.020 g, 0.026 mmol) was dissolved in 0.5 mL of anhydrous dimethylformamide and treated with 4-azidobenzoic acid N-hydroxysuccinimide ester (0.007 g, 0.025 mmol) and triethylamine (0.0025 g, 0.025 mmol, 0.0034 mL). After three hours the reaction mixture was diluted with 200 mL of ethyl acetate and washed with 2×100 mL of water, 1N hydrochloric acid, and brine. The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was dissolved in 0.5 mL of chloroform and precipitated with 70 mL of hexanes, filtered and dried in vacuo; 0.012 g (61%) mp 123-6°C; 1 H-NMR (300 MHz, CDCl3)δ0.85 (d, J=8 Hz, 3H, 10-CH3), 0.94 (d, J=8 Hz, 3H, 14-CH3), 1.15 (m, 1H, H-13), 1.63 (s, 3H, 8-CH3), 1.85 (m, 1H, H-15), 1.95 (s, 3H, 2-CH3), 2.35 (pent, J=8 Hz, 2H, 3' azetidine CH2), 2.6 (t, J=8 Hz, 2H, α-alanyl CH2), 2.7-2.9 (m, 2H, H-15 and H-10), 3.26 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.56 (m,1 H, β-alanyl CH2), 3.70 (m, 1H, H-12), 3.82 (m, 1H, β-alanyl CH2), 4.4-4.9 (m, 7H, H-6, 2' and 4' azetidine CH2, NH2), 5.10 (d, J=12 Hz, 1H, H-11), 5.3 (br m, 1H, H-9), 5.53 br s, 1H, H-7), 5.79 (t, J=9, 1H, H-5), 6.45 (t, J=9, 1H, H-4), 6.91 (s, 1H, H-19), 6.9-7.0 (m, 2H, H-3, NH), 6.98 (d of ABq, J=10 Hz, 2H, aromatic CH), 7.75 (d of ABq, J=10 Hz, 2H, aromatic CH), 8.16 (br s, 2H, alanyl NH2), 9.38 (s, 1H, NH-22).
PAC 17-Azetidin-1-yl-11-acetyl-17-demethoxygeldanamycin17-Azetidin-1-y-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride in a flame dried flask under nitrogen and treated with acetic anhydride (0.070 g, 0 683 mmol, 0.064 mL), DMAP (0.042 g, 0.341 mmol) and triethylamine 0.105 g (1.04 mmol, 0.145 mL) at room temperature. After 3 hours the mixture was diluted with 200 mL of methylene chloride and washed with 100 mL of water and 2×100 mL of brine. The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to a residue; 0.30 g. The residue was flash chromatographed on 120 g of silica gel with 2.5% methanol in chloroform to afford pure product, 0.120 g, which was recrystallized from 10 mL of toluene; 0.080 g (37%) mp 195° C.(dec); 1 H-NMR (300 MHz, CDCl3)δ0.93 (m, 6H, 14-CH3 and 10-CH3), 1.1-1.3 (m, 2H, H-13), 1.55 (m, 1H, H-14), 1.65 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 1.96 (s, 3H, acetyl CH3), 2.0 (m, 1H, H-15), 2.35 (pent, J=8 Hz, 2H, 3'-azetidine CH2), 2.6-2.85 (m, 2H, H-15, H-10), 3.29 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 3.60 (sept, J=8 Hz, 1H, isopropyl CH), 3.63 (m, 1H, H-12), 4.45 (d, J=8 Hz, 1H, H-6), 4.55 (t, J=8 Hz, 4H, 2' and 4' azetidine CH2), 4.73 (br s, 2H, NH2), 5.0 (m, 1H, H-11), 5.75 (d, J=11 Hz, 1H, H-9), 5.41 (br s, 1H, H-7), 5.78 (t, J=9 Hz, 1H, H-5), 6.46 (t, J=9 Hz, 1H, H-4), 6.91 (s, 1H, H-19), 7.10 (m, J=9 Hz, 1H, H-3), 9.34 (s, 1H, NH-22); m/z 650. (M++Na); IR (KBr, cm-1) 1735, 1685, 1645; Analysis calculated for C33 H45 N3 O9 :C, 63.14; H, 7.26; N, 6.69%. Found: C, 63.36; H, 6.94; N, 6.55%.
PAC 17-Azetidin-1-yl-11-aminocarbonyl-17-demethoxygeldanamycinPrepared in the manner of Example 61 from 17-azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341 mmol); yield 0.083 g (39%) mp 168-171°C; 1 H-NMR (300 MHz, CDCl3)δ0.98(d, J=8Hz, 3H, 10-CH3), 1.01 (d, J=8Hz, 3H, 14-CH3), 1.3 (br m, 2H, H-13), 1.73 (s, 3H, 8-CH3), 1.75 (br m, 1H, H-14), 2.02 (s, 3H, 2-CH3), 2.15 (m, 1H, H-15), 2.40 (pent, J=8 Hz, 2H, 3'-azetidine CH2), 2.67 (m, 1H, H-15), 2.87 (m, 1H, H-10), 3.36 (s, 6H, OCH3), 3.60 (m, 1H, H-12), 4.39 (br m, 2H, NH2), 4.5 (br d, J=9 Hz, 3H, H-6, NH2), 4.64 (br t, J=8 Hz, 6H, 2' and 4' azetidine CH2, NH2), 4.86 (m, 1H, H-11), 5.35 (d, J=12 Hz, 1H, H-9), 5.40 (br s, 1 H, H-7), 5.83 (br t, J=9 Hz, 1H, H-5), 6.54 (t, J=9 Hz, 1H, H-4), 6.97 (s, 1H, H-19), 7.21 (br m, 1H, H-3), 9.36 (s, 1H, NH-22); m/z 629. (M+); IR (KBr, cm-1) 1720, 1686, 1648 1533,1475; Analysis calculated for C32 H44N4 O9.H2 O: C, 59.42; H, 7.61; N, 8.66%. Found: C, 59.67; H, 6.81; N, 8.38%.
PAC 17-Allylamino-11-isopropylsulfamylcarbonyl-17-demethoxygeldanamycin17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.080 mg, 0.564 mmol, 0.049 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, isopropyl amine (0.066 g, 1.13 mmol, 0.096 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL of chloroform and extracted with 10 mL of water. The aqueous layeir was back extracted with 3×100 mL of chloroform. The pooled organic layers were extracted with 3×75 mL of 1N NaOH. The combined basic layers were washed with 3×100 mL of chloroform. The aqueous layer was acidified to pH 3 with 1 N hydrochloric acid and extracted with 3×100 ml of chloroform. These latter organic extracts were pooled, washed with 2×100 mL of brine, dried with sodium sulfate, filtered and evaporated in vacuo to a solid, 0.213 g. Flash column chromatography on silica gel eluted with 5% methanol in chloroform yielded pure title compound which was dissolved in 1 mL of chloroform and precipitated with hexanes, filtered and dried in vacuo; yield 0.061 g (25%) mp 137-139°C; 1 H-NMR (300 MHz, CDCl3)δ0.94 (d, 3H, J=8 Hz, 1-CH3), 0.98 (d, 3H, J=8Hz, 14-CH3), 1.1(m, 6H, isopropyl CH3),1.3-1.55 (br m, 2H, H-13), 1.65 (s, 3H, 8-CH3), 1.70 (br m, 1H, H-14), 1.95 (s, 3H, 2-CH3), 2.13 (m, 1H, H-15), 2.27 (dd, J=7 Hz, 16 Hz, 1H, H-15), 3.00 (m, 1H, H-10), 3.25 and 3.27 (br s, 6H, OCH3), 3.5 (m, 1H, isopropyl CH), 3.57 (br m, 1H, H-12), 4.05 (br t, 2H, allylic CH2), 4.43 (br m, 1H, H-6), 4.7 (br m, 2H, NH2), 4.9 (br s, 1H, NH) 5.02 (br d, J=11 Hz, 1H, H-11), 5.2 (br d, 2H, vinylic CH2), 5.38 (br m, 2H, H-7 and H-9), 5.75 (t, J=9 Hz, 1H, H-5), 5.85 (m, 1H, vinylic CH), 6.27 (br t, 1H, NH), 6.45 (t, J=9 Hz, 1H, H-4), 7.03 (br m, 1H, H-3), 7.10 (s, 1H, H-19), 9.30 (s, 1H, NH-22); m/z 772. (M++Na); IR (KB r, cm-1) 1737, 1690, 1645; Analysis calculated for C35,H51 N5 O11 S∅5H2 O: C, 55.39; H, 6.91; N, 9.23%. Found: C, 55.36; H, 6.95; N, 9.19%.
The compounds of Examples 68 and 69 were prepared by the method of Example 67 from the appropriate 17-demethoxy-geldanamycin.
PAC 17-β-Fluoroethylamino-11-isopropysulfamylcarbonyl-17-demiethoxygeldana mycinYield 0.122 g (38%) mp 142-146°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.93 (d, 3H, J=8Hz, 10-CH3), 0.97 (d, 3H, J=8Hz, 14-CH3), 1.07 (d, J=8 Hz, 6H, isopropyl CH3), 1.36 (br m, 1H, H-13), 1.46 (br m, 1H, H-13), 1.63 (br s, 4H, 8-CH3 and H-14), 1.94 (s, 3H, 2-CH3), 2.1 (br m, 1H, H-15), 2.82 (dd, J=7 Hz, 16 Hz, 1H, H-15), 2.95 (br m, 1H, H-10), 3.24 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.49 (sept, J=8 Hz, 1H, isopropyl CH), 3.59 (br m, 1H, H-12), 3.77 (two br d m, J=23 Hz, 2H, α-ethyl CH2), 4.43 (br s, 1H, H-6), 4.56 (two br d t, J=47 Hz 7 Hz, 2H, β-ethyl CH2), 4.8 (br m, 2H, NH2), 5.02 (br d, 2H, H-11 and NH), 5.75 (t, J=9 Hz, 1 H, H-5), 5.86 (br d, 2H, H-7 and H-9), 6.25 (br t, 1H, NH), 6.45 (t, J=9 Hz, 1H, H-4), 7.00 (br s, 1H, H-3), 7.10 (s, 1H, H-19), 7.55 (br s, 1H, NH), 9.25 (s, 1H, NH-22); m/z 778. (M++Na); IR (KBr, cm-1) 1735,1690,1645,1590,1480; Analysis calculated for C34 H50 FN5 O11 S: C, 60.69; H, 6.96; N, 7.07%. Found: C, 60.23; H, 6.99; N, 7.02%.
PAC 17-β-Cyanoethylamino-11-isopropylsulfamylcarbonyl-17-dernethoxygeldana mycinYield 0.037 g (11%) mp 150-154°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.98 (d, 6H, J=8 Hz, 10-Me and 14-Me), 1.08 (d, J=8 Hz, 6H, isopropyl CH3), 1.37 (br m, 1H, H-13), 1.5 (br t, 1H, H-13), 1.65 (s, 3H, 8-Me), 1.75 (br m, 1H, H-14), 1.95 (s, 3H, 2-Me), 2.04 (m, 1 H, H-15), 2.66 (t, J=8 Hz, 2H, β-ethyl CH2), 2.78 (m, 1H, H-15), 3.00 (br m, 1H, H-10), 3.26 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.50 (sept, J=8 Hz, 1H, isopropyl CH), 3.56 (br m, 1H, H-12), 3.77 (br m, 2H, α-ethyl CH2), 4.40 (br d, J=9 Hz, 1H, H-6), 4.75 (br m, 2H, NH2), 4.93 (br s, 1H, NH), 4.98 (br d, 1H, H-11), 5.34 (br m, 2H, H-7 and H-9), 5.76 (t, J=9 Hz, 1H, H-5), 5.96 (br t, 1H, NH), 6.45 (t, J=9 Hz, 1H, H-4), 7.00 (br s, 1H, H-3), 7.13 (s, 1H, H-19), 7.38 (br s, 1H, NH), 9.15 (s, 1H, NH-22); m/z 785. (M++Na); IR (KBr, cm-1) 2320, 1730, 1690, 1640, 1580, 1480; Analysis calculated for C35 H50 N6 O11.1.25H2 O: C, 54.78; H, 6.63; N, 10.95%. Found: C, 54.75; H, 6.16; N, 10.71%.
PAC 17-Azetidin-1-yl-11-isopropyisulfamylcarbonyl-17-demethcoxygeldanamycin17-Azetidin-1-yl-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) was added dropwise during 10 minutes. After stirring for two hours in the cold, isopropylamine (0.044 g, 0.75 mmol, 0.064 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL of methylene chloride and extracted with 2×100 mL of 1 N NaOH The combined basic layers were washed with 3×150 mL of methylene chloride and then acidified to pH 3 with 1 N hydrochloric acid. The acidic aqueous layer was extracl:ed with 3×150 mL of methylene chloride. These latter organic extracts were pooled, dried with sodium sulfate, filtered and evaporated in vacuo to a solid, 0.121 g which was dissolved in 1 mL of methylene chloride and precipitated with hexanes, filtered and dried in vacuo; 0.110 9 (43%) mp 14548°C; 1 H-NMR (300 MHz, CDCl3)δ0.9(d, J=8 Hz, 3H, 14-CH3), 0.96 (d, J=8 Hz, 3H, 10-CH3), 1.14 (d, J=8 Hz, 6H, isopropyl CH3), 1.3 (m, 1H, H-13), 1.5 (m, 1H, H-13), 1.6 (m, 1H, H-14), 1.64 (s, 3H, 8-CH3), 1.94 (s, 3H, 2-CH3), 2.0 (m, 1H, H-15), 2.36 (p, J=8 Hz, 2H, 3' azetidine CH2), 2.73 (dd, J=8 Hz and 16 Hz, 1H, H-15), 2.9 (m, 1H, H-10), 3.25 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.52 (sept, J=8 Hz, 1H, isopropyl CH), 3.63 (m, 1H, H-12), 4.43 (m, 1H, H-6), 4.57 (t, J=8 Hz, 4H, 2' and 4' azetidine CH2), 4.78 (br s, 2H, NH2), 5.0 (br s, 1 H, H-11), 5.86 (m, 2H, H-7 and H-9), 5.75 (t, J=9 Hz, 1H, H-5), 6.45 (t, J=9 Hz, 1H, H-4), 6.9 (s, 1H, H-19), 6.95 (m, J=9 Hz, 1H, H-3), 7.45 (m, 1H, NH), 9.35 (s, 1H, NH-22); m/z 772. (M++Na); IR (KBr, cm-1) 1735, 1685, 1645; Analysis calculated for C35 H51 N5 O11 S. 1.25H2 O: C, 54.43; H, 6.98; N, 9.07%. Found: C, 54.42; H, 6.54; N, 8.73%.
PAC 17-β-Cyanoethylamino-4.5-dihydro-11-isopropylsulfamylcarbonyl-17-demet hoxygeldanamycinThe title compound was prepared by the method of Example 70 from the compound of Example 11.
Yield 0.087 g (46%) mp 128-132°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.92 (d, J=8 Hz, 3H, 10-CH3), 0.93 (d, J=8 Hz, 3H, 14-CH3), 1.07 (d, J=8 Hz, 3H, isopropyl CH3), 1.09 (d, J=8 Hz, 3H, isopropyl CH3),1.17 (br m, 1H, H-13),1.36 (br t, 1H, H-13), 1.43 (s, 3H, 8-CH3), 1.46 (br m, 1H, H-14), 1.58 (m, 2H, H-5), 1.75 (s, 3H, 2-CH3), 2.00 (dd, J=14 Hz and 6 Hz, 1H, H-15), 2.23 (m, 2H, H-4), 2.56 (t, J=8 Hz, 2H, β-ethyl CH2), 2.77 (m,1 H, H-15), 3.06 (br m,1 H, H-10), 3.25 (s, 3H, OCH), 3.27 (s, 3H, OCH3), 3.35 (br m, 1 H, H-12), 3.47 (sept, J=8 Hz, 1H, isopropyl CH), 3.66 (br m, 2H, α-ethyl CH2), 4.54.63 (br m, 3H, H-6, NH2 and NH), 4.85 (d, J=6 Hz, 1 H, H-7), 5.05 (br s, 1 H H-7), 5.74 (d, J=9 Hz, 1 H, H-9), 5.87 (br t, 1H, NH), 6.26 (t, J=7 Hz, 1H, H-3), 7.05 (s, 1H, H-19), 7.40 (br s, 1H, NH), 9.00 (s, 1H, NH-22); m/z 787 (M++Na); IR (KBr, cm-1) 2320, 1730, 1690, 1645, 1580, 1480; Analysis calculated for C35 H52 N6 O11 S∅25H2 O: C, 54.71; H, 6.75; N, 10.93%. Found: C, 54.48; H, 6.88; N, 10.68%.
PAC 17-Azetidin-1-yl-11-(4'-azidophenyl)sulfamylcarbonyl-17-demethoxygeldanamyc in17-Azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.250 g, 0.427 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.099 mg, 0.704 mmol, 0.061 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, 4-azidoaniline (0.126 g, 0.938 mmol) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was evaporated to dryness and the residue flash chromatographed on 120 g silica gel with 3% methanol in chloroform affording pure product which was dissolved in 1 mL of chloroform and precipitated with hexanes; Yield 0.059 g (17%), mp 152-154°C; 1 H-NMR (300 MHz, CDCl3)δ0.85 (d, J=8 Hz, 3H, 14-CH3), 0.94 (d, J=8 Hz, 3H, 10-CH3), 1.2 (m, 1H, H-13), 1.36-1.7 (m, 2H, H-13 and H-14), 1.6 (s, 3H, 8-CH3), 1.94 (br s, 4H, 2-CH3 and H-15), 2.35 (pent, J=8 Hz, 2H, 3'-azetidine CH2), 2.65-2.9 (br m, 2H, H-10 and H-15), 3.24 (br s, 6H, OCH3), 3.64 (m, 1H, H-1 2), 4.46 (br s, 1H, H-6), 4.55 (t, J=8 Hz, 4H, 2' and 4' azetidine CH2), 4.85-5.1 (br s, 2H, NH2 and H-7), 5.85 (br s, 1H, H-11), 5.48 (br s, 1H, H-9), 5.77 (br t, J=9 Hz, 1H, H-5), 6.45 (t, J=9 Hz, 1H, H-4), 6.86 (s, 1H, H-19), 6.8-7.15 (m, 5H, H-3 and aromatic CH), 7.8 (v br d s, 1H, NH), 9.35 (s, 1H, NH-22); m/z 847. (M++Na); IR (KBr, cm-1) 2108, 1737, 1689, 1647, 1584, 1481; Analysis calculated for C38 H48 N8 O11 S.1.5H2 O: C, 53.57; H, 5.86; N, 13.15%. Found: C, 53.70; H, 5.57; N, 13.02%.
PAC 17-Allylamino-11-azetidin-1-ylsulfamylcarbonyl-17-demethoxygeldanamycin17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) wvas added dropwise during 10 minutes. After stirring for one hour in the cold, azetidine (0.043 g, 0.75 mmol, 0.051 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was evaporated to a residue and flash column chromatographed on 60 g silica gel eluted with 69:1:30 ethyl acetate:methanol:hexanes to yield pure target compound which was dissolved in 1 mL of chloroform, precipitated with hexanes and dried in vacuo; Yield 0.102 g (40%) mp 134-137°C; 1 H-NMR (300 MHz, CDCl3)δ0.92 (d, 3H, J=8Hz, 10-CH3), 1.01 (d, 3H, J=8Hz, 14-CH3), 1.4 (br m, 1H, H-13), 1.5 (br m, 2H, H-13 and H-14), 1.65 (s, 3H, 8-CH3), 1.95 (s, 3H, 2-CH3), 2.13 (m, 1H, H-15), 2.05-2.2 (m, 3H, H-15 and azetidine 3'-CH2), 2.78 (dd, J=6 Hz and 15 Hz, 1H, H-15), 2.93 (m, 1H, H-10), 3.26 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.63 (br m, 1H, H-12), 3.95-4.05 (br m, 6H, allylic CH2 and azetidine 2' and 4' CH2), 4.45 (br s, 1 H, H-6), 4.7 (br m, 2H, NH2), 5.02 (br d, J=11 Hz, 1H, H-11), 5.2 (m, 2H, vinylic CH2), 5.4 (br m, 2H, H-7 and H-9), 5.73-5.93 (m, 2H, H-5 and vinylic CH), 6.25 (br t, 1H, NH), 6.45 (t, J=9 Hz, 1H, H-4), 7.03 (br m, 1H, H-3), 7.10 (s, 1H, H-19), 9.32 (s, 1H, NH-22); m/z 769. (M++Na); IR (KBr, cm-1) 1734, 1691, 1645 1579, 1474; Analysis calculated for C35 H49 N5 O11 S∅75H2 O: C, 55.21; H, 6.69; N, 9.19%. Found: C, 55.19; H, 6.18; N, 9.20%.
PAC 17-Azetidin-1-yl-11-piperazinylsulfamylcarbonyl-17-demethioxygeldanamycin17-Azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.50 g, 0.854 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.133 mg, 0.939 mmol, 0.082 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, piperazine (0.162 g, 1.88 mmol) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was evaporated to dryness and the residue flash chromatographed on 200 g silica gel with 20% methanol in chloroform affording pure product which was dissolved in 5 mL of chloroform and precipitated with 150 mL of hexanes; Yield 0.161 g (24%), mp 180-182°C; 1 H-NMR (300 MHz, CDCl3)δ0.86(m, 3H, 14-CH3), 0.9 (m, 3H, 10-CH3), 1.6 (s, 3H, 8-CH3), 1.94 (br s, 2-CH3), 2.35 (pent, J=8 Hz, 2H, 3'-azetidine CH2), 3.25 (br s, 6H, OCH3), 3.64 (m, 1H, H-12), 4.46 (br s, 1H, H-6), 4.6 (t, J=8 Hz, 4H, 2' and 4' azetidine CH2), 6.43 (br t, 1H, H4), 6.9 (s, 1H, H-19), 9.35 (s, 1H, NH-22), other protons observed but not well defined or assignable; m/z 799. (M++Na); IR (KBr, cm-1) 1734, 1689, 1646, 1600, 1471; Analysis calculated for C33 H52 N6 O1 S.2H2 O: C, 53.19; H, 6.94; N, 10.34%. Found: C, 52.90; H, 6.81; N, 10.13%.
PAC 17-Azetidin-1-yl-11-(4'-methyl-1 '-piperazinyl)-sulfamylcarbonyl-17-demethoxy-geldanamycin17-Azetidin-1-yl-17-demethoxygeldanamycin, the title com pound of Example 18, (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloricde and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, N-methylpiperazine (0.075 g, 0.75 mmol, 0.083 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL of chloroform and extracted with 100 mL. of water and 2×100 mL of brine. The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to a solid, 0.280 g. This was flash chromatographed con silica gel with 10% methanol in chloroform affording pure product: yield 0.114 g (42%) mp 147-49° C.; 1 H-NMR (300 MHz, CDCl3)δ1.11 (d, J=8 Hz, 3H, 14-CH3), 1.21 (d, J=8 Hz, 3H, 10-CH3), 1.55 (m, 1H, H-13), 1.72 (m, 1H, H-13), 1.83 (m, 1H, H-14), 1.86 (s, 3H, 8-CH3), 2.2 (br s, 4H, 2-CH3 and H-15), 2.53 (s, 3H, N-CH3), 2.60 (br t, J=8 Hz, 2H, 3'-azetidine CH2), 2.70 (br s, 4H, piperazinyl CH2), 2.9-3.1 (m, 2H, H-10 and H-15), 3.53 (s, 6H, OCH3), 3.86 (m, 1H, H-12), 4.69 (br s, 1H, H-6), 4.82 (t, J=8 Hz, 4H, 2'and 4' azetidine CH2), 5.15 (br s, 2H, NH2), 5.72 (br s, 1H, H-7), 5.57 (br d, 1H, H-11), 5.66 (br s, 1H, H-9), 6.00 (t, J=9 Hz, 1H, H-5), 6.68 (t, J=9 Hz, 1H, H-4), 7.15 (s, 1H, H-19), 7.24 (br s, 1H, H-3), 7.45 (s, 1H, NH), 9.60 (s, 1H, NH-22); m/z 813. (M++Na); IR (KBr, cm-1) 1738, 1688, 1646, 1583, 1471; Analysis calculated for C37 H54 N6 O11 SeH2 O: C, 54.94; H, 6.97; N, 10.39%. Found: C, 54.92; H, 6.87; N, 10.2S%.
PAC 17-Allylamino-11-keto-17-demethoxygeldanamycin17-Allylamino-17-demethoxygeldanamycin (90 mg, 0.15 mmol) was dissolved in CHCl3 (4 mL) to which was added the Dess-Martin periodinane (382 mg, 0.90 mmol) and the reaction heated to reflux. After 1 hour the reaction was complete and the reaction mixture diluted with CHCl3. The organic layer was washed with aqueous Na2 S2 O3, saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was removed by evaporation and the residue recrystallized from ethyl acetate/hexanes to give 17-allylamino-11-keto-17-demethoxygeldariamycin, yield 84 mg (96%), as light red crystals, mp 112-118°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.02 (d, 3 H, J=7Hz), 1.25 (d, 3 H, J=7Hz), 1.48 (m, 2 H), 1.75 (m, 1H), 1.80 (s, 3 H), 1.98 (s, 3 H), 2.32 (dd, 1H, J=14 Hz, 5 Hz), 2.58 (dd, 1H, J=14 Hz, 7 Hz), 3.29 (overlapping s, 6 H), 3.66 (m, 1), 4.08 (m, 3H), 4.28 (d, 1H, J=8 Hz), 4.82 (br exchangeable, 2 H), 5.18-5.3 (m, 3 H), 5.55 (d, 1 H, J=9 Hz), 5.83-6.0 (m, 3 H), 6.83 (br exchangeable, 1 H), 6.49 (t, 1 H, J=11 Hz), 6.92 (d, 1 H, J=11 Hz), 7.19 (s, 1 H), 9.22 (s, 1 H); mass spectrum m/z 585 (M+2); Analysis calculated for C31 H41 N3 O8∅5 (ethyl acetate): C, 63.14; H, 7.23; N, 6.69%. Found: C, 63.19; H, 7.06; N, 6.92%.
The 11-keto compounds of Examples 77-87 were prepared by oxidation of the appropriate 17-amino substituted 17-demethoxygeldanamycins acccordingtothe method of Example 76.
PAC 17-Cyclopropylamino-11-keto-17-demethoxygeldanamycinMp 110-115°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.75-0.135 (m, 4 H), 1.03 (d, 3 H, J=7 Hz), 1.24 (d, 3 H, J=7 Hz), 1.72 (m, 1 H), 1.79 (s, 3 H), 1.98 (s, 3 H), 2.78 (m, 3 H), 3.32 (s, 3 H), 3.4-3.5 (m, 4 H), 4.08 (m, 2 H), 4.28 (d, 1 F,, J=8 Hz), 4.81 (br exchangeable, 2 H), 5.15 (s, 1 H), 5.57 (d, 1 H, J=10 Hz), 5.71 (t, 1 H, J=7 Hz), 6.26 (br s, 1 H), 6.51 (t, 1 H, J=12 Hz), 6.92 (d, 1 H, J=12 Hz), 7.15 (s, 1 H), 9.22 (s, 1 H); mass spectrum m/z 606 (M+Na)
PAC 17-Isopropylamino-11-keto-17-demethoxygeldanamycinMp 105-111 °C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.02 (d, 3 H, J=7 Hz), 1.25 (overlapping doublets, 9 H), 1.48 (m, 2 H), 1.75 (m, 1 H), 1.80 (s 3 H), 1.98 (s, 3 H), 2.27 (dd, 1 H, J=14 Hz, 5 Hz), 2.66 (dd, 1 H, J=14 Hz, 7 Hz), 3.32 (overlapping s, 6 H), 3.67 (m, 1 H), 3.98 (m, 1 H), 4.09 (t, 1 H, J=5 Hz), 4.38 (d, 1 H, J=9 Hz), 4.82 (br exchangeable, 2 H), 5.17 (s, 1 H), 5.54 (d, 1 H, J=9 Hz), 5.83 (t, 1 H, J=7 Hz), 6.17 (d, 1 H, J=9 Hz), 6.49 (t, 1 H, J=11 Hz), 6.92 (d, 1 H , J=11 Hz), 7.17 (s, 1 H), 9.27 (s, 1 H); mass spectrum m/z 587 (M+2); Analysis calculated for C31 H43 N3 O8∅2CH2 Cl2 : C, 62.22; H, 7.20; N,6.98%. Found: C, 62.16; H, 7.0; N, 6.75%.
PAC 17-Methylamino-11-keto-17-demethoxygeldanamycinMp 108-120°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.05 (d, 3 H, J=7 Hz), 1.23 (d, 3 H, J=7 Hz), 1.48 (m, 2 H), 1.80 (s, 3 H), 1.97 (s, 3 H), 2.43 (dd, 1 H, J=14 Hz, 5 Hz), 2.68 (dd, 1 H, J=14 Hz, 7 Hz), 3.17 (s, 3 H), 3.30 (overlapping s, 6 H), 3.68 (m, 1 H), 4.11 (t, 1 H, J=5 Hz), 4.32 (d, 1 H, .J=8 Hz), 4.80 (br exchangeable, 2 H), 5.21 (s, 1 H), 5.53 (d, 1 H, J=10 Hz), 5.83 (t, 1 H, J=7 Hz), 6.51 (t, 1 H, J=12 Hz), 6.92 (d, 1 H, J=10 Hz), 7.19 (s, 1 H), 3.28 (s, 1 H); mass spectrum m/z 580 (M+Na).
PAC 17-(2'-Hydroxyethylamino)-11-keto-17-demethoxygeldanamycinMp 108-111 °C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.07 (d, 3 H, J=7 Hz), 1.25 (d, 3 H, J=7 Hz), 1.51 (m, 2 H), 1.76 (m, 1 H), 1.81 (s, 3 H), 1.98 (s, 3 H), 2.32 (dd, 1 H, J=14 Hz, 4 Hz), 2.63 (dd, 1 H, J=14 Hz, 7 Hz), 3.34 (overlapping s, 6 H), 3.62 (m, 3 H), 3.88 (t, 2 H, J=5 Hz), 4.09 (t, 1 H, J=5 Hz), 4.28 (d, 1 H, J=9 Hz), 4.8 (br exchangeable, 2 H), 5.18 (s, 1 H), 5.53 (d, 1 H, J=13 Hz), 5.79 (d, 1 H, J=8 Hz), 6.48 (t, 1 H, J=14 Hz), 6.92 (d, 1 H, J=14 Hz), 7.18 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 589 (M+2); Analysis calculated for C30 H41 N3 O9 : C, 61.32; H, 7.03; N, 7.15%. Found: C, 60.96; H, 7.12; N, 6.90%.
PAC 17-(2'-Methoxyethylamino)-11-keto-17-demethoxygeldanaycinMp 130-134°C (dec); 1 H-NMR (300 MHz, CDCl3) δ1.05 (d, 3 H, J=7 Hz), 1.24 (d, 3 H, J=7 Hz), 1.82 (m, 2 H), 1.85 (s, 3 H), 2.00 (s, 3 H), 2.34 (dd, 1 H, J=14 Hz, 5 Hz), 2.62 (dd, 1 H, J=14 Hz, 7 Hz), 3.33 (overlapping s, 6 H), 3.40 (s, 3 H), 3.6-3.7 (m, 5 H), 4.10 (m, 2 H), 4.31 (d, 1 H, J=9 Hz), 4.8 (br exchangeable, 2 H), 5.22 (s, 1 H), 5.55 (d, 1 H. J=10 Hz), 5.82 (t, 1 H, J=7 Hz), 6.49 (t, 1 H, J=12 Hz), 6.92 (d, 1 H, J=10 Hz), 7.18 (s, 1 H), 9.24 (s, 1 H); mass spectrum m/z 603 (M+2); Analysis calculated for C31 H43 N3 O9 : C, 61.79; H, 7.20; N, 6.98%. Found: C, 61.75; H, 7.02; N, 6.86%.
PAC 17-(2'-Methylthioethylamino)-11-keto-17-demethoxygeldanamycinMp 95-100°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.05 (d, 3 H. J=7 Hz), 1.23 (d, 3 H, J=7 Hz), 1.48 (m, 2 H), 1.80 (m, 1 H), 1.81 (s, 3 H), 1.95 (s, 3 H), 2.11 (s, 3 H), 2.32 (dd, 1 H, J=14 Hz, 5 Hz), 2.63 (dd, 1 H, J=14 Hz, 5 Hz), 2.76 (t, 2 H, J=7 Hz), 3.32 (overlapping s, 6 H), 3.67 (t, 2 H, J=7 Hz), 3.67 (single proton under triplet), 4.08 (t, 1 H, J=5 Hz), 4.37 (d, 1 H, J=7 Hz), 4.8 (br s, 2 H), 5.18 (s, 1 H), 5.52 (d, 1 H, J=9 Hz), 5.83 (apparent t, 1 H, J=9 Hz), 6.50 (t, 1 H, J=10 Hz), 6.92 (br d, 1 H, J=12 Hz), 7.19 (s, 1 H), 9.21 (s, 1 H); mass spectrum m/z 620 (M+2); Analysis calculated for C31 H43 N3 O8 S: C, 60.27; H, 7.02; N, 6.80%. Found: C, 60.16; H, 6.82; N, 6.67%.
PAC 17-(2'-Fluoroethylamino)-11-keto-17-demethoxygeldanamycinMp 99-105°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.04 (d, 3 H, J=7 Hz), 1.25 (d, 3 H, J=7 Hz), 1.50 (m, 2 H), 1.80 (m, 1 H), 1.81 (s, 3 H), 1.99 (s, 3 H), 2.31 (dd, 1 H, J=14 Hz, 5 Hz), 2.62 (dd, 1 H, J=14 Hz, 9 Hz), 3.31 (overlapping s, 6 H), 3.68 (dd, 1 H, J=9 Hz, 7 Hz), 3.77 (m, 1 H), 3.84 (m, 1 H), 4.10 (t, 1 H, J=6 Hz), 4.30 (d, 1 H, J=8 Hz), 4.54 (t, 1 H, J=5 Hz), 4.70 (t, 1 H, J=5 Hz), 5.19 (s, 1 H), 5.54 (d, 1 H, J=9Hz), 5.83 (t, 1 H, J=9 Hz), 6.28 (t, 1 H, J=6 Hz), 6.5) (t, 1 H, J=12 Hz), 6.93 (d, 1 H, J=12 Hz), 7.20 (s, 1 H), 9.17 (s, 1 H); mass spectrum m/z 591 (M+2); Analysis calculated for C30 H40 N3 O8.1/12CHCl3 : C, 60.26; H, 6.84; N, 7.01%. Found: C, 60.57; H, 6.54; N, 6.87%.
PAC 17-(2'-Cyanoethylamino)-11-keto-17-demethoxygeldanamycinMp 102-107°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.07 (d 2 H, J=7 Hz), 1.25 (d, 3 H, J=7 Hz), 1.53 (m, 2 H), 1.80 (m, 1 H), 1.81 (s, 3H), 2.00 (s, 3 H), 2.27 (dd, 1 H, J=14 Hz, 5 Hz), 2.58 (dd, 1 H, J=14Hz, 6 Hz), 2.69 (t, 2 11, J=8 Hz), 3.32 (s, 3 H), 3.33 (s, 3 H), 3.71 (dd, 1 H, J=9 Hz, 7 Hz), 3.80 (q, 2 H, J=7 Hz), 4.07 (m, 1 H), 4.29 (d, 1 H, J=8 Hz), 4.8 (br s, 2 H), 5.17 (s, 1 H), 5.55 (d, 1 H, J=9 Hz), 5.84 (apparent t, 1 H, J=9 Hz), 6.02 (t, 1 H, J=6 Hz), 6.51 (t, 1 H, J=11 Hz), 6.94 (br d, 1 H, J=12 Hz), 7.22 (s, 1 H), 9.09 (s, 1 H); mass spectrum m/z 619 (M+Na); Analysis calculated for C31 H40 N4 O8 : C, 62.40; H, 6.76; N, 9.39%. Found: C, 61.81; H, 6.45; N, 9.06%.
PAC 17-Azetidin-1-yl-11-keto-17-demethoxygeldanamycinMp 112-116°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.02 (d, 3 H, J=7 Hz), 1.37 (d, 3 H, J=7 Hz), 1.48 (m, 2 H), 1.67 (m, 1 H), 1.82 (s, 3 H), 1.97 (s, 3 H), 2.22 (dd, 1 H, J=14 Hz, 5 Hz), 2.42 (m, 2 H), 2.58 (dd, 1 H, J=14 Hz, 7 Hz), 3.30 (overlapping s, 6 H), 3.61 (m, 1 H), 5.15 (t, 1 H, J=5 Hz), 4.17 (d, 1 H, J=8 Hz), 4.62 (t, 4 H, J=7 Hz), 4.80 (br s, 2 H), 5.19 (s, 1 H), 5.51 (d, 1 H, J=10 Hz), 5.76 (t, 1 H, J=10 Hz), 6.48 (t, 1 H, J=12 Hz), 6.90 (br d, 1 H, J=12 Hz), 6.97 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 583 (M+); Analysis calculated for C31 H41 N3 O8 : C, 63.79; H, 7.08; N, 7.20%. Found: C, 63.83; H, 7.11; N, 6.84%.
PAC 17-(3'-Hydroxyazetidin-1-yl)-11-keto-17-demethoxygeldanamycinMp 145°C (foam); 1 H-NMR (300 MHz, CDCl3)δ1.0 (d, 3 H, J=4 Hz), 1.2-1.3 (m, 6 H), 1.4 (m, 2 H), 1.7 (m, 1 H), 1.8 (s, 3 H), 2.15 (s, 2 H), 2.2 (d, 1 H, J=4 Hz), 2.5 (m, 1 H), 3.3 (2 singlets, 6 H), 3.6 (m, 1 H), 3.8 (br s, 1 H), 4.15 (m, 1 H), 4.3 (d, 1 H, J=7 Hz), 4.354.5 (m, 2 H), 4.5-4.9 (m, 3 H), 5.0-5.2 (m, 3 H), 5.5 (d, 1 H, J=7 Hz), 5.8 (m, 1 H), 6.5 (t, 1 H, J=10 Hz), 6.9 (d, 1 H, J=14 Hz), 7.0 (s, 1 H), 9.2 (s, 1 H); mass spectrum m/z 622 (M+2); Analysis calculated for C31 H43 N3 O9.H2 O: C, 60.28; H, 7.02; N, 6.80%. Found: C, 60.76; H, 7.10; N, 6.36%.
PAC 17-(3'-Methoxyazetidin-1-yl)-11-keto-17-demethoxygeldanamycinMp 128°C (foam); 1 H-NMR (300 MHz, CDCl3)δ1.0 (d, 3 H, J=7 Hz), 1.25 (m, 6 H), 1.45 (m, 2 H), 1.6-1.85 (m, 4 H, contains methyl singlet), 1.9-2.1 (m, 4 H, contains methyl singlet), 2.1-2.3 (m, 1 H), 2.95-3.25 (m, 1 H), 3.3 (m, 9 H, contains 3 methyl singlets), 3.6 (m, 1 H), 4.04.3 (m, 3 H), 4.354.5 (m, 2 H), 4.6-4.8 (m, 2 H), 5.1 (br s, 2 H), 5.2 (s, 1 H), 5.5 (d, 1 H, J=10 Hz), 5.8 (m, 1 H), 6.5 (t, 1 H, J=12 Hz), 6.9 (d, 1 H, J=12 Hz), 7.0 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 636(M+Na); Analysis calculated for C32 H43 N3 O9 : C, 62.63; H, 7.06; N, 6.85%. Found: C, 62.23; H, 7.19; N, 6.70%.
PAC 17-Methylamino-11-(2'-morpholinoethylamino)-17-demethoxygeldanamycinIn a dry flask, sodium triacetoxyborohydride (152 mg, 0.72 mmol) in dichloroethane (4 mL) was sonicated until a fine suspension was formed. The mixture was removed from the sonicator and treated with N-aminoethylmc rpholine (47 μ, 0.36 mmol) and a few crystals of sodium sulfate. 11-Keto-17-methylamino-17-demethoxygeldanamycin (100 mg, 0.18 mmol) was then added and the mixture stirred at room temperature for 24 hours. The reaction mixture was washed with saturated sodium carbonate and brine and then dried over sodium sulfale. The solvent was removed by rotary evaporation and the crude product purified by column chromatography (silica gel, 10% methanol in methylene chloride) to give the title compound as a purple solid; Yield 87 mg, (71%), mp 119-120°C; 1 H-NMR (300 MHz, CDCl3)δ0.90 (d, 3 H, J=7 Hz), 1.00 (d, 3 H, J=7 Hz), 1.42 (m, 2 H), 1.59 (m, 1 H), 1.65 (s, 3 H), 1.95 (s, 3 H), 2.03 (br s 1 H), 2.25 (dd, 1 H, J=8 Hz), 2.68 (m, 3 H), 2.81 (m, 2 H), 3.15 (d, 3 H, J=7 Hz), 3.22 (s, 3 H), 3.28 (s, 3 H), 3.52 (m, 1 H), 3.62 (t, 4 H, J=4 Hz), 4.44 (br d, 1 H, J=10 Hz), 4.75 (br s, 1 H), 5.40 (s, 1 H), 5.55 (d, 1 H, J=10 Hz), 5.78 (dd, 1 H, J=8 Hz), 6.28 (d, 1 H, J=7 Hz), 6.45 (t, 1 H, J=13 Hz), 7.00 (m, 1 H), 7.05 (s, 1 H), 9.40 (s, 1 H); mass spectrum m/z 6,72 (M+).
The compounds of Examples 89-95 were prepared from 11-keto-17-(methylamino)-17-demethoxygeldanamycin and the appropriate amines using the reductive amination method of Example 88.
11-Benzylamino-17-methylamino-17-demethoxygeldanamycin Mp 123-126° C.; 1 H-NMR (300 MHz, CDCl3)δ0.91 (d, 3H, J=8 Hz), 0.98 (d, 3 H, J=8 Hz), 1.35 (m, 1 H), 1.58 (m, 2 H), 1.66 (m, 1 H), 1.70 (s, 3 H), 1.95 (s, 3 H), 2.32 (dd, 1 H, J=8 Hz), 2.75 (dd, 1 H, J=8 Hz, 12 Hz), 2.93 (m, 1 H), 3.08 (s, 4 H), 3.12 (d, 3 H, J=8Hz), 3.15 (s, 6 H), 3.46 (d, 1 H, J=8Hz), 3.61 (d, 1 H, J=24Hz), 3.78 (d, 1 H, J=24 Hz), 4.30 (d, 1 H, J=8 Hz), 4.75 (br s, 2 H), 5.35 (s, 1 H), 5.70 (m, 2 H), 6.28 (d, 1 H, J=8 Hz), 6.43 (t, 1 H, J=12 Hz), 7.01 (br d, 1 H, J=16 Hz), 7.08 (s, 1 H), 7.20 (m, 5 H), 9.42 (s, 1 H); mass spectrum m/z 649 (M+1).
PAC 11-Cyclopropylamino-17-methylamino-17-demethoxygeldanamycinMp 120-123°C; 1 H-NMR (300 MHz, CDCl3)δ0.30 (m, 4 H), 0.93 (d, 3 H, J=8 Hz), 1.02 (d, 3 H, J=8 Hz), 1.40 (m, 2 H), 1.72 (s, 3 H), 1.80 (br s, 1 H), 1.99 (s, 3 H), 2.15 (s, 1 H), 2.32 (dd, 1 H, J=8Hz, 13 Hz), 3.00 (m, 1 H), 3.18 (d, 3 H, J=7Hz), 3.28 (s, 3 H), 3.30 (s, 3 H), 3.57 (m, 1 H), 4.39 (d, 1 H, J=8 Hz), 4.84 (br s, 2 H), 5.63 (d, 1 H, J=8 Hz), 5.80 (dd, 1 H, J=8 Hz, 8 Hz), 6.32 (d, 1 H, J=7 Hz), 6.51 (t, 1 H, J=13 Hz), 7.01 (br d, 1 H, J=17 Hz), 7.09 (s, 1 H), 9.44 (s, 1 H); mass spectrum m/z 600 (M+1).
PAC 11-Isoamylamino-17-methylamino-17-demethoxygeldanarnycinMp 108-110°C; 1 H-NMR (300 MHz, CDCl3)δ0.90 (d, 3 H, J=8 Hz), 1.00 (d, 3 H, J=8 Hz), 1.22-1.60 (m, 5 H), 1.63 (m, 1 H), 1.65 (s, 3 H), 1.95 (s, 3 H), 2.29 (dd, 1 H, J=7 Hz), 2.53 (m, 1 H), 2.75 (m, 2 H), 2.90 (m, 1 H), 3.13 (d, 3 H, J=7 Hz), 3.23 (s, 3 H), 3.28 (s, 3 H), 3.52 (m, 1 H), 4.90 (br s, 2 H), 5.35 :s, 1 H), 5.60 (br d, 1 H, J=8), 5.75 (dd, 1 H, J=8 Hz), 6.30 (d, 1 H, J=7 Hz), 6.43 (t, 1 H, J=12 Hz), 7.02 (s, 1 H), 7.09 (br s, 1 H), 9.38 (s, 1 H); mass spectrum m/z 629 (M+1)
PAC 11-(2'-Hydroxyethylamino)-17-methylamino-17-demethoxygeldanamycinMp (oil); 1 H-NMR (300 MHz, CDCl3)δ0.95 (d, 3 H, J=7 Hz), 1.09 (d, 3 H, J=7 Hz), 1.45 (m, 1 H), 1.58 (m, 2 H), 1.72 (s, 3 H), 2.00 (s, 3 H), 2.30 (dd, 1 H, J=8 Hz), 3.02 (m, 9 H), 3.20 (d, 3 H, J=7 Hz), 3.28 (s, 3 H), 3.35 (s, 3 H), 3.62 (m, 3 H), 4.55 (br s, 1 H), 4.90 (br s, 2 H), 5.40 (br s, 1 H), 5.63 (d, 1 H, J=10 Hz), 5.81 (dd, 1 H, J=8 Hz), 6.36 (d, 1 H, J=7 Hz), 6.50 (t, 1 H, J=13 Hz), 7.08 (m, 1 H), 7.12 (s, 1 H), 9.40 (s, 1 H); mass spectrum m/z 603 (M+1).
PAC 11-(3'-Dimethylaminopropylamino)-17-methylamino-17-demethoxygeldanamycinMp 105-108°C; 1 H-NMR (300 MHz, CDCl3)δ0.95 (d, 3 H, J=7 Hz), 1.03 (d, 3 H, J=7 Hz), 1.48 (m, 1 H), 1.65 (m, 3 H), 1.70 (s, 3 H), 1.98 (s, 3 H), 2.20 (s, 6 H), 2.28 (m, 3 H), 2.65 (m, 1 H), 2.70 (m, 2 H), 2.84 (dd, 1 H, J=7 Hz), 2.90 (m, 1 H), 3.20 (d, 3 H, J=7 Hz), 3.29 (s, 3 H), 3.33 (s, 3 H), 3.57 (m, 1 H), 4.48 (d, 1 H, J=13 Hz), 4.80 (br s, 2 H), 5.41 (br s, 1 H), 5.62 (br d, 1 H, J=13 Hz), 5.81 (dd, 1 H, J=8 Hz), 6.32 (d, 1 H, J=7 Hz), 6.49 (t, 1 H, J=13 Hz), 7.09 (m, 1 H), 7.10 (s, 1 H), 9.43 (s, 1 H); mass spectrum m/z 644 (M+ +1).
PAC 11-Allylamino-17-methylamino-17-demethoxygeldanamycinMp 123-125°C; 1 H-NMR (300 MHz, CDCl3)δ0.95 (d, 3 H, J=7 Hz), 1.03 (d, 3 H, J=7Hz), 1.41 (m, 1 H), 1.52 (m, 1 H), 1.72 (s, 3 H), 1.84 (m, 2 H), 2.00 (s, 3 H), 2.36 (dd, 1 H, J=7 Hz), 2.80 (m, 2 H), 3.00 (m, 1 H), 3.20 (d, 3 H, J=7 Hz), 3.25 (s, 3 H), 3.32 (s, 3 H), 3.58 (m, 1 H), 4.42 (d, 1 H, J=10 Hz), 4.80 (br s, 2 H), 5.08 (dd, 2 H, J=16 Hz), 5.40 (s, 1 H), 5.65 (d, 1 H, J=13 Hz), 5.83 (m, 2 H), 6.32 (d, 1 H, J =7 Hz), 6.50 (t, 1 H, J=13 Hz), 7.05 (m, 1 H), 7.10 (s, 1 H), 9.45 (s, 1 H); mass spectrum m/z 599 (M+ +1).
PAC 17-Azetidin-1-yl-11-oximino-17-demethoxygeldanamycinTo a solution of 17-azetidin-1-y-11-keto-17-demethoxyg edanamycin (0.10 g, 0.17 mmol) in ethanol was added a solution of hydroxylamine hydrochloride (0.10 g, 1.42 mmol) and triethylamine (0.2 mL) in ethanol. The reaction mixture was stirred at room temperature for 2.5 hours and thereafter the solvent was removed by rotary evaporation and the residue dissolved in CHCl3. The chloroform solution was washed with water, dried over sodium sulfate and the solvent removed by rotary evaporation. The residue was purified by column chromatography (silica gel, 15% acetone in CHCl3) to give 17-azetidino-11-oximino-17-demethoxygeldanamycin (70 mg, 68 %), as a purple powder. Mp 130-145°C (dec); 1 H-NMR (300 MHz, CDCl3)δ0.98 (d, 3 H, J=7 Hz), 1.17 (d, 3 H, J=7 Hz), 1.37 (m, 2 H), 1.54 (m, 1 H), 1.81 (s, 2 1), 1.95 (s, 3 H), 2.25 (dd, 1 H, J=14 Hz, 4 Hz), 2.41 (m, 2 H), 2.61 (dd, 1 H, J=14 Hz, 3 Hz), 3.20 (s, 3 H), 3.28 (s, 3 H), 4.02 (m, 2 H), 4.13 (d, 1 H, J=8 Hz), 4.65 (t 1 H, J=8 Hz), 5.01 (br exchangeable, 2 H), 5.09 (s, 1 H), 5.37 (br d, 1 H, J=10 Hz), 5.74 (t, 1 H, J=10 Hz), 6.45 (t, 1 H, J=12 Hz), 6.89 (br s, 1 H), 6.97 (s, 1 H), 9.27 (s, 1 H); mass spectrum m/z 586 (M -2); Analysis calculated for C31 H42 N4 O8 : C, 62.19; H, 7.07; N, 9.36%. Found: C, 61.76; H, 6.88; N, 9.14%.
The compounds of Examples 96-99 were prepared according to the method of Example 95 from the appropriate 11-keto-17-demethoxygeldanamycin.
PAC 17-(2'-Methoxyethylamino)-11-oximino-17-demethoxygeldanamycinMp 119-127°C (dec); 1 H-NMR (300 MHz, CDCl3)δ1.03 (d, 3 H, J=7 Hz), 1.18 (d, 3 H, J=7 Hz), 1.39 (m, 1 H), 1.84 (s, 3 H), 1.86 (m, 1 H), 1.98 (s, 3 H), 2.32 (dd, 1 H, J=14Hz, 4Hz), 2.68 (dd, 1 H, J=14 Hz, 7 Hz), 3.21 (s, 3 H), 3.27(s, 3 H), 3.38 (s, 3 H), 3.58 (m, 2 H), 3.62 (m, 2 H), 3.95 (m, 2 H), 4.12 (d, 1 H, J=8 Hz), 4.90 (br s, 1 H), 5.11 (s, 1 H), 5.38 (br d, 1 H, J=8 Hz), 5.75 (t, 1 H, J=10 Hz), 6.50 (m, 2 H), 6.9 (br s, 1 H), 7.17 (s, 1 H), 9.25 (s, 1 H); mass spectrum m/z 616 (M+).
PAC 17-CyClopropylamino-11-oximino-17-demethoxygeldananycinMp (amorphous); 1 H-NMR (300 MHz, CDCl3)δ0.7-0.9 (m, 4 H), 1.0 (d, 3 H, J=7 Hz), 1.2 (d, 3 H, J=7 Hz), 1.3-1.6 (m, 3 H), 1.8 (s, 3 H), 1.95 (m, 1 H), 2.0 (s, 3 H), 2.7 (m, 1 H), 2.9 (m, 2 H), 3.2 (s, 3 H), 3.3 (s, 3 H), 4.05 (br s, 2 H), 4.15 (d, 1 H, J=7 Hz), 5.13 (d, 2 H, J=10 Hz), 5.45 (d, 1 H, J=10 Hz), 5.8 (t, 1 H, J=10 Hz), 6.3 (d, 1 H, J=3 Hz), 6.48 (t, 1 H, J=10 Hz), 6.9 (br d, 1 H, J=10 Hz), 7.08 (m, 1 H), 7.15 (s, 1 H), 9.28 (br s, 1 H); mass spectrum m/z 621 (M+Na); Analysis calculated for C31 H42 N4 O8∅5 H2 O: C, 61.27; H, 7.13; N, 9.22%. Found: C, 61.74; H, 7.25; N, 8.71%.
PAC 17-lsopropylamino-11-oximino-17-demethoxygeldanamycinMp 158-160°C; 1 H-NMR (300 MHz, CDCl3)δ1.0 (d, 3 H, J=7 Hz), 1.15 (d, 3 H, J=7 Hz), 1.2 (d, 3 H, J=7 Hz), 1.3 (d, 3 H, J=7 Hz), 1.45-1.6 (br t, 1 H), 1.7-1.9 (m, 4 H), 2.0 (s, 3 H), 2.2 (br d, 1 H, J=14), 2.75 (t, 1 H, J=14 Hz), 3.15 (s, 3 H), 3.25 (s, 3 H), 3.84.05 (m, 3 H), 4.1 (d, 1 H, J=10), 5.1 (s, 1 H), 5.25-5.5 (br d, 3 H), 5.7 (t, 1 H, J=10 Hz), 6.2 (d, 1 H, J=10 Hz), 6.4 (t, 1 H, J=1 Hz), 6.75 (br d, 1 H), 7.1 (s, 1 H), 9.25 (br s, 1 H); mass spectrum m/z 623 (M+Na); Analysis calculated for C31 H44 N4 O8.1.5 H2 O: C, 59.32; H, 7.55; N, 8.93%. Found: C, 59.27H, 7.07; N, 8.66%.
PAC 17-Allylamino-11-oximino-17-demethoxygeldanamycinMp 135°C; mass spectrum m/z 621 (M+Na).
Moyer, Mikel Paul, Gallaschun, Randall James, Schnur, Rodney Caughren
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